The mission of the Neuroscience Division is to discover cellular and molecular mechanisms that govern normal development and function of the nervous system. This knowledge is then applied to expand understanding of how neurological disorders arise and may be treated. Current focus is on movement disorders such as Parkinson’s, ALS, peripheral neuropathies that damage neurons and myelin, as well as Neurofibromatosis, a genetic disorder that promotes tumorigenesis in the nervous system.

The division’s researchers are conducting cutting-edge research on:

Faculty work in a collaborative environment together with partners within UCF and in the community to translate this knowledge into new therapies for neurological disorders. Faculty collaborate with UCF researchers in Mechanical Engineering and the Prosthetic Interface Initiative (http://www.ucf.edu/faculty/cluster/prosthetic-interfaces/), Nanoscience Technology Center, College of Optics and Photonics, and Psychology. Working together with scientists and physicians from the Veterans Affairs Medical Center, Nemours Children’s Hospital, Sanford Burnham Prebys Medical Discovery Institute, and Florida Hospital’s Translational Research Institute enrich the clinical and translational research environment in the Neuroscience Division.

Division Faculty

    Dr. Ella Bossy-Wetzel
  • Title: Professor
  • Office: BBS 414
  • Phone: 407.266.7139
  • Research to identify critical events that cause neurodegeneration particularly those associated with mitochondrial dysfunction. ALS, mitochondria
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  • Biography:

    Dr. Bossy-Wetzel joined UCF in 2007 as tenured Professor.  She trained at Cold Spring Harbor Laboratory and the University of California, San Francisco and the Pasteur Institute of Paris, France.  Prior to joining UCF, Dr. Bossy-Wetzel was an Assistant Professor at the Burnham Institute for Medical Research in La Jolla, California.  She has received numerous prestigious awards from organizations including the Human Frontier Science Program Organization, the European Molecular Biology Organization, Swiss National Funds, National Institutes of Health, the American Parkinson’s Disease Foundation, and the Hereditary Disease Foundation.  Her laboratory is currently funded by a grant from the National Institute for Neurological Disease and Stroke.  Her publications have received over 14100 citations with an h-index of 40. She serves yearly on numerous grant review boards for the National Institutes of Health, the National Science Foundation, and the Swiss National Funds.

    MISSION

    The mission of our laboratory is to identify the critical events that cause neurodegeneration. Our ultimate goal is to improve the lives of patients and their families by developing effective treatments that can cure or prevent neurodegenerative diseases.

    CHALLENGE

    While physicians can recognize and identify the clinical symptoms of most neurodegenerative disorders, current treatments merely treat the symptoms and cannot cure the disease. Therefore, new discoveries are urgently needed that will lead to therapies that can prevent the relentless and progressive neuronal loss. Our laboratory addresses this challenge by identifying the key events that cause neurodegeneration. We are working on hereditary and sporadic disorders including Alzheimer’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and Optic Atrophy. We focus on mitochondria primarily, because mitochondrial injury is an early and central event in many if not all neurodegenerative diseases, and thus represents an opportunity for therapeutic intervention.

    APPROACH

    To embark on this challenge and to map the key events that push neurons into degenerative cascades, we have developed sophisticated, quantitative time-lapse imaging techniques. We use these systems to decipher the temporal and spatial sequence of events related to neurodegeneration in living neurons, and to test potential therapeutic agents that may interfere with this process. In addition to primary neurons our laboratory uses mouse models of neurodegeneration and human patient samples. Our approach is interdisciplinary and includes cell biology, biochemistry, genetics, biophysics, electron microscopy, and structure biology.

    MITOCHONDRIA IN NEURONS

    Mitochondria in nerve cells are crucial for energy supply and the maintenance of effective communication networks between neurons, needed for learning and memory. The body uses twenty percent of its energy to maintain normal brain function. Mitochondria must supply most of this energy. Thus, it comes as no surprise that mitochondrial injury can have devastating effects on the brain and nervous system. Mitochondria also serve as sinks for calcium ions that accumulate after neuronal firing and neurotransmission. Additionally, injured mitochondria act as reactors. Similar to damaged power plants, they can leak hazardous materials such as cytochrome c or free radicals that can ignite subsequent nerve cell injury and, ultimately, result in neuronal death.  To meet the intense energy requirements, each neuron has several hundred mitochondria. Mitochondria in healthy neurons resemble long filaments, equally spaced along nerve processes similar to train tracks, permitting effective energy transmission across extreme distances that can reach a meter in motor neuron axons. Besides their often cable-like morphology, mitochondria in neurons are remarkably dynamic, traveling along nerve processes and undergoing cycles of mitochondrial fission and fusion.

    MITOCHONDRIAL FISSION AND FUSION

    A conserved battery of large dynamin-related GTPases with opposing functions orchestrates mitochondrial fission and fusion. Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and Mitofusin-1 and -2 (Mfn1,2) and Optic Atrophy 1 (OPA1) mediate mitochondrial fusion. Interestingly, patients suffering of the neurodegenerative disorders Charcot-Marie-Tooth syndrome type 2A, a peripheral neuropathy, and dominant optic atrophy, an optic neuropathy, carry mutations in Mfn2 and OPA1, respectively. These findings underscore the importance of mitochondrial fusion in neuronal function and suggest that tilting the balance of mitochondrial fission and fusion toward continuous fission can set off a neurodegenerative cascade. Mitochondrial fusion may protect neurons by preventing depletion of metabolites or mitochondrial DNA. Without fusion deficiencies may become manifest, thus leading to a vicious cycle.

    MITOCHONDRIAL FRAGMENTATION IN NEURODEGENERATION

    During brain injury neurons release glutamate, an excitatory neurotransmitter that causes excessive activation of glutamate receptors of the NMDA subtype. Activation of NMDA receptors leads to rapid calcium influx and nitric oxide (NO) accumulation. Too much NO can combine with superoxide anions to form highly neurotoxic peroxynitrite. We recently discovered that NO triggers profound mitochondrial fission accompanied by ultrastructural changes of mitochondria, autophagy, ATP decline, and free radical production. Blocking mitochondrial fission and increasing mitochondrial fusion delayed neuronal cell death. Our results suggest that mitochondrial fission occurs early and contributes to ischemic stroke and the pathogenesis of Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, optic nerve damage, and motor neuron disease including ALS.

    Recent Publications

    1. Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E. Cell Death Differ. 2012 Nov. 9
    2. Purification, crystallization and X-ray diffraction analysis of human dynamin-related protein 1 GTPase-GED fusion protein. Klinglmayr E, Wenger J, Mayr S, Bossy-Wetzel E, Puehringer S. Acta Crystallogr. Sect F Struct Biol Cyrst Commun. 2012 Oct.1; 68: 1217-21.
    3. Mutant SOD1 (G93A) triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1a. Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Neurobiol Dis 2012 Jul. 20
    4. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E.Nat Med. 2011 Feb 20.
    5. Impact of nitric oxide on metabolism in health and age-related disease. Knott AB,Bossy-Wetzel E. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:126-33.
    6. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basañez G, Meda P, Martinou JC. Cell. 2010 Sep 17;142(6):889-901.
    7. S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer’s disease. Bossy B, Petrilli A, Klinglmayr E, Chen J, Lütz-Meindl U, Knott AB, Masliah E, Schwarzenbacher R, Bossy-Wetzel E.J Alzheimers Dis. 2010;20 Suppl 2:S513-26.
    8. New insights into mitochondrial structure during cell death.Perkins G, Bossy-Wetzel E, Ellisman MH. Exp Neurol. 2009 Aug;218(2):183-92. Epub 2009 May 21. Review.
    9. Clearing the brain’s cobwebs: the role of autophagy in neuroprotection.Bossy B, Perkins G, Bossy-Wetzel E.Curr Neuropharmacol. 2008 Jun;6(2):97-101.
    10. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Liot G, Bossy B, Lubitz S, Kushnareva Y, Sejbuk N, Bossy-Wetzel E. Cell Death Differ. 2009 Jun;16(6):899-909. Epub 2009 Mar 20.
    11. Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Knott AB, Bossy-Wetzel E.Ann N Y Acad Sci. 2008 Dec;1147:283-92. Review.
    12. Assessing mitochondrial outer membrane permeabilization during apoptosis.Dave Z, Byfield M, Bossy-Wetzel E. Methods. 2008 Dec;46(4):319-23. Epub 2008 Oct 26.
    13. Assessing mitochondrial morphology and dynamics using fluorescence wide-field microscopy and 3D image processing. Song W, Bossy B, Martin OJ, Hicks A, Lubitz S, Knott AB, Bossy-Wetzel E. Methods. 2008 Dec;46(4):295-303. Epub 2008 Oct 24.
    14. Mutant huntingtin and mitochondrial dysfunction. Bossy-Wetzel E, Petrilli A, Knott AB. Trends Neurosci. 2008 Dec;31(12):609-16. Epub 2008 Oct 24. Review.
    15. Nitric oxide in health and disease of the nervous system. Knott AB, Bossy-Wetzel E.Antioxid Redox Signal. 2009 Mar;11(3):541-54. Review.
    16. Mitochondrial fragmentation in neurodegeneration. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Nat Rev Neurosci. 2008 Jul;9(7):505-18. Review.
    17. Mitochondrial swelling measurement in situ by optimized spatial filtering: astrocyte-neuron differences. Gerencser AA, Doczi J, Töröcsik B, Bossy-Wetzel E, Adam-Vizi V.Biophys J. 2008 Sep;95(5):2583-98. Epub 2008 Apr 18.
    18. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B, Bossy-Wetzel E, Bennett MV, Pypaert M, Hickman JA, Smith PJ, Hardwick JM, Jonas EA. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74. Epub 2008 Feb 4.
    19. A Golgi fragmentation pathway in neurodegeneration.Nakagomi S, Barsoum MJ,Bossy-Wetzel E, Sütterlin C, Malhotra V, Lipton SA. Neurobiol Dis. 2008 Feb;29(2):221-31. Epub 2007 Sep 7.
    20. ALS: astrocytes take center stage, but must they share the spotlight? Knott AB,Bossy-Wetzel E.Cell Death Differ. 2007 Dec;14(12):1985-8. Epub 2007 Oct 5. No abstract available
    21. Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Yuan H, Gerencser AA, Liot G, Lipton SA, Ellisman M, Perkins GA, Bossy-Wetzel E.Cell Death Differ. 2007 Mar;14(3):462-71. Epub 2006 Oct 20

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    Dr. Zixi (Jack) Cheng
  • Title: Associate Professor
  • Office: BMS 230
  • Phone: 407.823.1505
  • Studies on sleep apnea, diabetes and aging-induced cardiac neuropathy. Brain-Heart Connections, Autonomic Nervous System
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  • Biography:

    Cardiovascular diseases are the leading cause of mortality and morbidity and many of the cardiovascular disorders (hypertension, cardiomyopathy, decreased cardiac reflexes, and cardiac failure) are intimately associated with aging, sleep apnea (intermittent hypoxia), and diabetes mellitus. Among these disorders, the reduction of autonomic control of the heart rate in patients is very dangerous and it is commonly used as a risk predictor for life threatening arrhythmia which causes sudden death. However, the neural mechanisms involved in cardiac neuropathy of aging, intermittent hypoxia, and diabetes-related cardiovascular morbidity, are poorly understood.  More specifically, precise physiological and anatomical assessments of reductions in autonomic control of the cardiovascular function and the underlying morphological reorganization of cardiac circuitry during aging, following intermittent hypoxia (sleep apnea), in chronic diabetes are currently poorly defined due to past technical limitations. Detailed characterization of the organization and reorganization of autonomic axons and terminals in cardiac tissues is an essential component towards increasing our understanding of aging-, chronic intermittent hypoxia-, and diabetes- related cardiac processes. The long-term goal of my research is first to study modifications of the cardiac functions and the changes of the neural circuitry in the brain-heart axis of aged, intermittent hypoxia-exposed, and diabetes in rat and mouse models at different ages (young, mid-age, and old) as well as to characterize cardiac nerve regeneration after denervation. Then, we will seek for medical interventions to prevent/reduce such pathological changes as well as to promote cardiac nerve regeneration.

    We will use the recent technological advances in my lab and my collaborators’ labs to test our leading hypothesis that functional changes, morphological reorganization, and enhanced ROS production of the parasympathetic nervous system occur at multiple sites within the brain-heart axis in intermittent hypoxia-exposed and chronic diabetic animals. Since advanced age is a strong risk factor for neuropathy, we further hypothesize that aging and diabetes/sleep apnea may interact to exacerbate deleterious processes.

    Technically, we have first successfully developed a combination of novel anatomical techniques, including microinjections, anterograde tracing, laser scanning confocal microscopy, and stereological counting strategies to qualitatively and quantitatively characterize vagal cardiac axons and terminals in rat hearts. Second, we have established a selective lesion protocol to dissect the functional roles of nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). Thirdly, we have obtained a unique transgenic mouse model of chronic type 1 diabetes (OVE26), thereby permitting detailed examination of functional and anatomical alterations in the chronic diabetic heart. Fourth, we have used a rather unique rodent model of intermittent hypoxia that closely mimics the behavioral, anatomical, and physiological consequences of obstructive sleep apnea. Therefore, we are able to examine the functional and anatomical alterations in chemoreceptor and baroreceptor reflexes.  Finally, we have established two physiological systems which will allow us to record aortic nerve activity in vivo and to patch-clamp baroreceptor neurons in the nodose ganglion of rats.

    Recent Publications

     

    1: Cheng ZJ. Vagal cardiac efferent innervation in F344 rats: Effects of chronic

    intermittent hypoxia. Auton Neurosci. 2016 Oct 29. pii: S1566-0702(16)30236-3.

    doi: 10.1016/j.autneu.2016.10.005. [Epub ahead of print] PubMed PMID: 27839717.

     

     

    2: Hatcher J, Gu H, Cheng ZJ. SOD1 Overexpression Preserves Baroreflex Control of

    Heart Rate with an Increase of Aortic Depressor Nerve Function. Oxid Med Cell

    Longev. 2016;2016:3686829. doi: 10.1155/2016/3686829. PubMed PMID: 26823951;

    PubMed Central PMCID: PMC4707341.

     

     

    3: Harris DM, Bellew C, Cheng ZJ, Cendán JC, Kibble JD. High-fidelity patient

    simulators to expose undergraduate students to the clinical relevance of

    physiology concepts. Adv Physiol Educ. 2014 Dec;38(4):372-5. doi:

    10.1152/advan.00063.2014. PubMed PMID: 25434023.

     

     

    4: Li L, Hatcher JT, Hoover DB, Gu H, Wurster RD, Cheng ZJ. Distribution and

    morphology of calcitonin gene-related peptide and substance P immunoreactive

    axons in the whole-mount atria of mice. Auton Neurosci. 2014 Apr;181:37-48. doi:

    10.1016/j.autneu.2013.12.010. PubMed PMID: 24433968.

     

    1. Gui L, Bao Z, Jia Y, Qin X, Cheng ZJ, Zhu J, Chen QH. Ventricular

    tachyarrhythmias in rats with acute myocardial infarction involves activation of

    small-conductance Ca2+-activated K+ channels. Am J Physiol Heart Circ Physiol.

    2013 Jan 1;304(1):H118-30. doi: 10.1152/ajpheart.00820.2011. PubMed PMID:

    23086994.

     

    6: Dayyat EA, Zhang SX, Wang Y, Cheng ZJ, Gozal D. Exogenous erythropoietin

    administration attenuates intermittent hypoxia-induced cognitive deficits in a

    murine model of sleep apnea. BMC Neurosci. 2012 Jul 3;13:77. doi:

    10.1186/1471-2202-13-77. PubMed PMID: 22759774; PubMed Central PMCID: PMC3412695.

     

     

     

    7: Lin M, Hatcher JT, Wurster RD, Chen QH, Cheng ZJ. Characteristics of single

    large-conductance Ca2+-activated K+ channels and their regulation of action

    potentials and excitability in parasympathetic cardiac motoneurons in the nucleus

    ambiguus. Am J Physiol Cell Physiol. 2014 Jan 15;306(2):C152-66. doi:

    10.1152/ajpcell.00423.2012. PubMed PMID: 24196530; PubMed Central PMCID:

    PMC3919986.

     

     

    8: Lin M, Hatcher JT, Chen QH, Wurster RD, Li L, Cheng ZJ. Maternal diabetes

    increases large conductance Ca2+-activated K+ outward currents that alter action

    potential properties but do not contribute to attenuated excitability of

    parasympathetic cardiac motoneurons in the nucleus ambiguus of neonatal mice. Am

    J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1070-8. doi:

    10.1152/ajpregu.00470.2010. PubMed PMID: 21248308; PubMed Central PMCID:

    PMC3094040.

     

     

    9: Lin M, Hatcher JT, Chen QH, Wurster RD, Cheng ZJ. Small conductance

    Ca2+-activated K+ channels regulate firing properties and excitability in

    parasympathetic cardiac motoneurons in the nucleus ambiguus. Am J Physiol Cell

    Physiol. 2010 Dec;299(6):C1285-98. doi: 10.1152/ajpcell.00134.2010. PubMed PMID:

    20739619; PubMed Central PMCID: PMC3774095.

     

     

    10: Lin M, Chen QH, Wurster RD, Hatcher JT, Liu YQ, Li L, Harden SW, Cheng ZJ.

    Maternal diabetes increases small conductance Ca2+-activated K+ (SK) currents

    that alter action potential properties and excitability of cardiac motoneurons in

    the nucleus ambiguus. J Neurophysiol. 2010 Oct;104(4):2125-38. doi:

    10.1152/jn.00671.2009. PubMed PMID: 20668269; PubMed Central PMCID: PMC2957455.

     

    For more publication information, please visit Pubmed.

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    Dr. Cristina Fernandez-Valle
  • Title: Professor
  • Office: BBS 249
  • Phone: 407.266.7033
  • Uncovering molecular mechanisms controlling normal and pathological development of Schwann cells. Translational science focused on target and drug discovery for development of Neurofibromatosis Type 2 therapies. Myelin, signal transduction
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  • Biography:

    My research is focused on understanding molecular mechanisms controlling peripheral nerve development with emphasis on regulation of growth and differentiation of Schwann cells into myelin-forming cells. Major pathways examined are transduction of extracellular matrix signals through integrin receptors and neuregulin signalling through erbB2/erbB3 receptors. The integration of these pathways with those regulating cytoskeleton organization through the rho family of GTPases is under study.

    We have found that schwannomin/merlin the product of the Neurofibromatosis type 2 gene is a direct binding protein with paxillin, an integrator of extracellular matrix and growth factor signalling with changes in the actin cytoskeleton. The interacting domain in schwannomin is mutated in humans with NF2 mutations and leads to tumor formation.

    The studies are conducted using primary Schwann cells in isolation or together with sensory neurons to study development of myelin in vitrol. These studies are funded by a long-standing grant from NIH/NINDS and have application for the understanding of various demyelinating diseases as well as abnormal growth of Schwann cells.
    Recent Publications

    1. Marisa A. FuseStephani Klingeman PlatiSarah S. BurnsChristine T. DinhOlena BrachoDenise YanRahul MittalRulong ShenJulia N. SoulakovaAlicja J. CopikXue Zhong LiuFred F. TelischiLong-Sheng ChangMaria Clara Franco and Cristina Fernandez-Valle. (2017) Combination Therapy With c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of MerlinDeficient Schwann Cells and Suppresses Growth of Schwannoma Cells. 
    2. Sparrow N*, Manetti M, Bott M, Bates, M, Bunge MB, Lambert, S, Fernandez-Valle C.  (2012) The Actin Severing Protein Cofilin is Downstream of Neuregulin Signaling and is Essential For Schwann Cell Myelination. J Neuroscience. 32:5284-97.
    3. Douglass. Sparrow, Bott, Fernandez-Valle, Dogariu. 2012Measuring Anisotropic Cell Motility on Curved Substrates. J Biophotonics (doi: 10.1002/jbio.201200089.)
    4. Manetti, Geden, Bott, Sparrow, Lambert, Fernandez Valle. 2012 Stability of the tumor suppressor merlin depends on its ability to bind paxillin LD3 and associate with β1 integrin and actin at the plasma membrane.   Biology Open (doi: 10.1242/bio.20122121; 1, 949-957.)
    5. Thaxton C*, Bott M, Walker B, Sparrow NA*, Lambert S, and Fernandez-Valle C.  2011. Schwannomin Promotes Process Extension and Determines Internodal Myelin Length. Mol Cell Neuroscience. 47:1-9.
    6. Iacovelli J, Lopera J, Bott M, Baldwin ME, Khaled A, Uddin N, Fernandez-Valle C (2007). Serum and forskolin cooperate to promote G1 progression in Schwann cells by differentially regulating cyclin D1, cyclin E1, and p27Kip expression. Glia 55(16):  1638-47.
    7. Thaxton C, Lopera J, Bott M, Fernandez-Valle C (2007) Neuregulin and laminin stimulate phosphorylation of the NF2 tumor supressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways.  Oncogene. doi: 10.1038/sj.onc.1210923.

    For more publication information, please visit Pubmed.

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    Dr. Yoon-Seong Kim, MD
  • Title: Associate Professor
  • Office: BBS 312
  • Phone: 407.266.7070
  • Elucidate the molecular mechanism underlying the pathogenesis of Parkinson's disease. Current focus is on DNA oxidative damage and its contribution to mutated α-syn through transcriptional mutagenesis.
  • Send an Email
  • Biography:

    My research explores the molecular mechanism underlying selective degeneration of the specific neuronal population in neurodegenerative disorders, especially Parkinson’s disease (PD).

    Although oxidative stress is considered as a major contributing factor in PD, molecular sources for ROS in PD remain poorly understood. Emerging evidence has demonstrated that NADPH oxidases, the specialized superoxide generating enzyme complex, play a key role in oxidative stress in various disease conditions in the central nervous system. We recently discovered that the NADPH oxidase 1 (NOX1)/Rac1 system is activated in dopaminergic neurons under various stress conditions and plays a key role in oxidative stress-mediated dopaminergic neuronal degeneration. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), a newly identified causative gene for PD, also increase Nox1 expression and ROS generation in DA cells. Together, our findings suggest that Nox1-derived superoxide generation in DA neurons is likely a common downstream event in idiopathic or genetic causes of PD. This research is currently supported by NIH and Michael J. Fox foundation.

    Recently, our lab has established paraquat-based rat PD model in which significant dopaminergic neuronal degeneration as well as alpha-synuclein aggregation, a key pathologic feature, are successfully observed. Using this novel animal model, our lab members are trying to discover the molecular mechanism governing Nox1/Rac1-derived oxidative stress in the nigrostriatal pathway and its effect on the genome-wide epigenetic regulation in PD.

    To efficiently achieve this research goals, my lab have established a number of important tools including adeno-associated viral (AAV) gene targeting and expression in vivo, real-time imaging of ROS generation in neurons, oxidative changed DNA immunoprecipitation (oxo-DIP) and target gene specific methyl-profiling.

    Recent Publications

    1. Campos, F. L., Carvalho, M. M., Cristovão, A. C., Je, G., Baltazar, G., Salgado, A. J., Kim, Y.-S., and Sousa, N. (2013) Rodent models of Parkinson’s disease: beyond the motor symptomatology. Frontiers in Behavioral Neuroscience 7, 175
    2. Chung, Y. C., Kim, Y.-S., Bok, E., Yune, T. Y., Maeng, S., and Jin, B. K. (2013) MMP-3 Contributes to Nigrostriatal Dopaminergic Neuronal Loss, BBB Damage, and Neuroinflammation in an MPTP Mouse Model of Parkinson’s Disease. Mediators of Inflammation 2013
    3. Cristóvão, A. C., Barata, J., Je, G., and Kim, Y.-S. (2013) PKCδ mediates paraquat-induced Nox1 expression in dopaminergic neurons. Biochemical and biophysical research communications 437, 380-385
    4. Lee, K., Im, J., Woo, J., Grosso, H., Kim, Y., Cristovao, A., Sonsalla, P., Schuster, D., Jalbut, M., and Fernandez, J. (2013) Neuroprotective and Anti-inflammatory Properties of a Coffee Component in the MPTP Model of Parkinson’s Disease. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics
    5. Choi DH, Cristóvão AC, Guhathakurta S, Lee J, Joh TH, Beal MF, Kim YS (2012) NADPH Oxidase 1-Mediated Oxidative Stress Leads to Dopamine Neuron Death in Parkinson’s Disease. Antioxid Redox Signal. 16, 1033-1045
    6. Choi DH, Kim YJ, Kim YG, Joh TH, Beal MF, Kim YS (2011) Role of matrix metalloproteinase 3-mediated alpha-synuclein cleavage in dopaminergic cell death. J Biol Chem  286, 14168-77
    7. Choi DH, Hwang O, Lee KH, Lee J, Beal F. and Kim YS (2010) DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress induced dopaminergic cell death. Antioxid Redox Signal 14, 2137-50.
    8. Cho Y, Son HJ, Kim EM, Choi JH, Kim ST, Ji IJ, Choi DH, Joh TH, Kim YS, Hwang O (2009) Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a       Dual Mechanism Involving MMP-3. Neurotox Res 16, 361-71
    9. Cristóvão AC, Choi DH, Baltazar G, Beal MF and Kim YS (2009) The role of NADPH oxidase-derived reactive oxygen species in paraquat-mediated dopaminergic cell death. Antioxid Redox Signal 11, 2105-18
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    Dr. Stephen J King
  • Title: Associate Professor
  • Office: BBS 214
  • Phone: 407.266.7108
  • Discovery based research that examines the role of molecular motors in intracellular transport. A focus of the lab is on a novel mouse model of CMT we have developed that is caused by a mutation in the dynein motor gene. Axonal transport and peripheral neuropathies
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  • Biography:

    Our ultimate goal is to understand how intracellular transport occurs and how defects in transport may lead to the onset and progression of neurodegenerative disease.  One cytoskeletal motor that plays an important role in intracellular transport is cytoplasmic dynein, which generates force as it moves toward the minus ends of microtubules. We have previously shown that the ability of cytoplasmic dynein to take multiple steps without dissociating from the microtubule, called processivity, is enhanced by the dynein activator, dynactin.  Our laboratory discovered that dynactin actually  contains two different microtubule-binding domains and that one of these, the basic domain, is required for dynactin to enhance dynein processivity.Processive long-range movements are especially important in the axonal processes of neurons where cytoplasmic dynein moves retrograde cargo over distances ranging from microns to meters.  Genetic lesions in components of the cytoplasmic dynein and dynactin motor machinery have been shown to alter axonal transport and in some cases to result in severe neurodegenerative diseases such as Perry syndrome, amyotrophic lateral sclerosis (ALS),  and distal spinal and bulbar muscular atrophy (dSBMA).  Our hypothesis is that the basic domain of dynactin p150 acts as a molecular tether to maintain contact between dynein, dynactin, cargo and the microtubule during motility events.We have expanded our interests beyond dynactin-microtubule interactions to also include regulation of dynein-based transport by additional mechanisms in an attempt to better understand the complexity of cellular dynein-based transport.  Our current research is suported by NIH and is testing our model of how dynactin functions in dynein-based cargo transport.  We will also determine the roles that additional cellular factors have in dynein-based cargo transport.  We will utilize both in vitro and in vivo assays of dynein and dynactin function to test our models for how dynein-based cargo transport normally occurs and how it may be altered during neurodegenerative disease.Recent Publications:

    1. Xu, J., B. J. Reddy, P. Anand, , Z. Shu, S. Cermelli, M. K. Mattson, S. K. Tripathy, M. T. Hoss, N. S. James, Stephen J. King, L. Huang, L. Bardwell, and S. P. Gross. (2012)  Casein kinase 2 reverses tail-independent inhibition of kinesin-1. (2012) Nature Communications, 3:754.  (PMID:22453827)
    2. Xu, J. Z. Shu, Stephen J. King, and S. P. Gross.  Tuning multiple motor travel via single motor velocity. (2012) Traffic. 13:1198-1205. (PMID:22672518)
    3. Sivagurunathan, S., R. R. Schnittker, D.S. Razafsky, S. Nandini, M. Plamann and Stephen J. King.  (2012) Analyses of dynein heavy chain mutations reveal complex interactions between dynein motor domains and cellular dynein functions. Genetics.  191:1157-1179. (PMID:22649085)
    4. Sivagurunathan, S., R. R. Schnittker, S. Nandini, M. Plamann and Stephen J. King. (2012) A mouse neurodegenerative dynein heavy chain mutation alters dynein motility and localization in Neurospora crassa. Cytoskeleton.  69:613-624. (PMID:22991199)
    5. Splinter, D., D. S. Razafsky, M. A. Schlager, A. Serra-Marques, I. Grigoriev, J. Demmers, N. Keijzer, K. Jiang, I. Poser, A. A. Hyman, C. C. Hoogenraad, Stephen J. King, and A. Akhmanova. BicD, dynactin and LIS1 cooperate in dynein recruitment to cellular structures. Molecular Biology of the Cell.  23:4226-4241.  (PMID: 22956769)
    6. Vershinin M., J. Xu, D. S. Razafsky, Stephen J. King, and S.P. Gross.  (2008)  Tuning microtubule-based transport through filamentous MAPs: the problem of dynein.  Traffic. 9:882-92.
    7. Bekker, J., J. Cloantonio, A. D. Stephens, W. Clarke, Stephen J. King, K. Hill, and R. Crosbie.  (2007) Direct interaction of Gas11 with microtubules: implications for the  dynein regulatory complex.  Cell Motility and the Cytoskeleton.  64:461-73.
    8. Dompierre, J.P., J. D. Godin, B. C. Charrin, F. P. Cordelieres, Stephen. J. King, S. Humbert, F. Saudou.  (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation.  Journal of Neuroscience. 27:3571-83.
    9. Vershinin, M., B.C. Carter, D.S. Razafsky, Stephen J. King, and S. P. Gross.  (2007)  Multiple-motor based transport and its regulation by Tau.  Proceedings of the National Academy of Sciences (PNAS).  104:87-92. PMCID: PMC1765483
    10. Kincaid, M.M., and Stephen J. King.  (2006)  Motors and their tethers: The role of secondary binding sites in processive motility.  Cell Cycle.  5:2733-2737. PMCID: PMC1850974
    11. Culver-Hanlon, T. L., S. A. Lex, A. D. Stephens, and Stephen J. King.  (2006)  A microtubule-binding domain in dynactin increases dynein processivity by skating along microtubules. Nature Cell Biology. 8:264-270.
View Full Profile
    Dr. Mohtashem Samsam
  • Title: Associate Professor
  • Office: HPA II 320
  • Phone: 407.823.4810
  • Pain and migraine as well as the role of inflammation in neurological and psychiatric disorders.
  • Send an Email
  • Biography:

    Dr. Mohtashem Samsam is an Associate Professor of Medicine and a faculty at the Burnett School of Biomedical Sciences and College of Medicine (COM). He joined UCF in fall 2004. He is teaching anatomy, clinical neuroanatomy, and clinical neuroscience to undergraduate, graduate, and medical students. Dr. Samsam studied Medicine in English language program of Albert Szent-Gorgyi Medical University, in Szeged, Hungary (1991- 1996) and received his PhD in Neurosciences from Dep. of cell biology and pathology, Faculty of Medicine, University of Salamanca, Spain, in 2002. He did his post-doc studies in Developmental Neurobiology in Neurology University Clinic, Wuerzburg, Germany (1999- 2002).
     
    Publishing several articles in headache and migraine during his MD and PhD studies he continued his post-doc studies examining the mechanism of neurodegeneration in animal models of inherited peripheral neuropathies and treatment of Charcot-Marie Tooth disorders using gene therapy and alteration of immune response. His research and scholarly activities are in migraine headaches and role of inflammation in neurological and psychiatric disorders.
     
    Dr. Samsam is the Editor in Chief of Neuro-Open Journal, http://openventio.org/EditorialBoard/Neuro.html; and he is an editor of several journals including the DATA Sets International (Dataset Papers in Medicine), Psychiatry: http://www.hindawi.com/journals/dpis/editors/psychiatry/; editor in Austin Journal of Biomedical Engineering, http://austinpublishinggroup.com/biomedical-engineering/editorialboard.php; and an editor in Science Domain International, Archives of Current Research International: http://sciencedomain.org/journal/41/editorial-board-members.
     
    He is the author of several book chapters and two textbooks.
     
    Dr. Samsam has developed several courses at undergraduate and graduate levels at UCF, and as a member of curriculum planning committee he was heavily involved in the development of many of the medical courses for LCME accreditation in 2006-2007.
     
    He received multiple awards during the past couple of years including the Golden Apple Excellence in Teaching Award & Professor of the Year, from UCF Premed-American Medical Student Association (AMSA) for 8 years in the row; the Excellence in Undergraduate Teaching Award, UCF, COM, 2009- 2010; the Scholarship of Teaching and Learning (SoTL) Award, UCF, COM, 2011-2012; the UCF Creed Award in Scholarship//med.ucf.edu/news/2012/05/dr-samsam-is-keeper-of-the-creed/, 2011-2012; and the Teaching Incentive Program (TIP) Award, UCF, COM, 2012- 2013.
     
    Dr. Samsam led (2013-2015) a STEM internship program in partnership with and funded by the Career Source of Central Florida (CSCF) that is being facilitated by the UCF office of experiential learning. The program provides senior undergraduate students an opportunity to work and do research in COM labs for 6-month supported by the CSCF: //med.ucf.edu/news/2014/07/collaboration-creating-on-the-job-research-training-career-opportunities/
     
    He is coordinating a similar program in UCF COM, the Florida Work Experience Program (FWEP), a UCF initiative coordinated and funded by the UCF Office of Experiential Learning to provide work and research experience to undergraduate students.
     
    Recent Publications

    1. Samsam M, Ahangari R. Neuromodulation in the treatment of migraine: Progress in nerve stimulation. Neuro Open J. 2017; 3(1): 9-22. doi:10.17140/NOJ-3-122.
    2. Samsam M. Neuromodulation and nonpharmacological treatment of migraine. Editorial. Neuro Open J. 2016; 3(1): e5-e10. doi: 10.17140/NOJ-3-e006.
    3. Samsam M., Targeting calcitonin gene-related peptide and its receptor by monoclonal antibody, new developments in the treatment of migraine. Editorial,Neuro Open J. 2015; 2: e6-e10. http://dx.doi.org/10.17140/NOJ-2-e004.
    4. Samsam M., Drugs against calcitonin gene-related peptide and its receptor used in the treatment of migraine: What are the new progresses? Neuro Open J. 2015; 2: 79-91. http://dx.doi.org/10.17140/NOJ-2-117.
    5. Samsam M, Ahangari R, Naser SA. Pathophysiology of autism spectrum disorders: Revisiting gastrointestinal involvement and immune imbalance.World J Gastroenterol. 2014 Aug 7;20(29):9942-9951.
    6. Samsam M.:Functionally Oriented Regional Anatomy, Hayden McNeil, MI, USA, 2nd edition, 2013, ISBN: 978-0-7380-5685-2.
    7. Samsam M.:Regional Anatomy Lab, an e-book atlas of anatomy, Great River Technologies & Thieme, IA, USA, 1st edition, 2013, ISBN: 978-1-61549-278-7.
    8. Samsam M.Central nervous system drugs in treatment of neurological disorders, editorial, Cent Nerv Syst Agents Med Chem. 2012, 12:153-7.
    9. Samsam M.Central nervous system acting drugs in treatment of migraine headache, Cent Nerv Syst Agents Med Chem. 2012, 12:158-72
    10. Samsam M.Role of inflammation in neurological and psychiatric disorders, editorial, AIAA-MC, 2010, 3: 166-169.
    11. Samsam M.,Coveñas R., Ahangari R., Yajeya J. Neuropeptides and other chemical mediators, and the role of anti-inflammatory drugs in primary headaches, AIAA-MC, 2010, 3: 170- 188.
    12. Samsam M.,Coveñas R., Ahangari R., Yajeya J.: Major neuroanatomical and neurochemical substrates involved in primary headaches. In: Neuroanatomy Research Advances; chapter 1; Editors: CE Flynn and BR Callaghan; Nova Science Publishers; New York; 2009; pp1- 58; ISBN: 978-60741-610-4.
    13. Samsam M.,Coveñas R., Ahangari R., Yajeya J., Narváez JA.: Role of neuropeptides in migraine headaches, experimental and clinical data, Focus on Neuropeptide Research, chapter 11; Editor: R. Covenas; Transworld Research Network; India, released in 2008; ISBN: 978-81-7895-291-8.
    14. Samsam M.,Coveñas R., Ahangari R., Yajeya J. and Narváez JA.: Role of neuropeptides in migraine; where do they stand in the latest expert recommendations in migraine treatment? Drug Development Research, 2007, 68: 298- 314.
    15. Ruhlman T., Ahangari R., Devine A., Samsam M., Daniell H.: Expression of cholera toxin B-proinsulin fusion protein in lettuce and tobacco chloroplasts – oral administration protects against development of insulitis in non-obese diabetic mice, Plant Biotechnol J., 2007, 5: 495- 510.

     

View Full Profile
    Dr. Amber Southwell
  • Title: Assistant Professor
  • Office: BBS 327
  • Phone: 407.266.7134
  • Neurodegenerative disease modeling and preclinical development of experimental therapeutics and biomarkers with a focus on Huntington Disease
  • Send an Email
  • Biography:

    Dr. Amber L. Southwell, Assistant Professor, Burnett School of Biomedical Sciences, Division of Neuroscience, has been working in preclinical therapy development for Huntington disease (HD) for 15 years. In 2009 she earned her PhD at the California Institute of Technology working with Dr. Paul Patterson to develop an intrabody gene therapy for HD. From 2009-2016, she did postdoctoral research at the University of British Columbia with Dr. Michael Hayden where she developed several novel mouse models of HD, a selective mutant huntingtin gene silencing therapy, and a CSF biomarker for brain huntingtin. She began her laboratory research group at UCF in January 2017, where she continues these studies while also applying her successful strategies for HD to other inherited neurodegenerative diseases.

     

    Selected Publications

     

    1. Southwell AL, Skotte NH, Villanueva EB, Østergaard ME, Gu X, Kordasiewicz HB, Kay C, Cheung D, Xie Y, Waltl S, Dal Cengio L, Findlay-Black H, Doty CN, Petoukhov E, Iworima D, Slama R, Ooi J, Pouladi MA, Yang WX, Swayze EE, Seth PP, Hayden MR. (2017) A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles. Hum Mol Genet. 26(6):1115-1132 PMID: 28104789
    2. Southwell AL*, Smith A, Kay C, Sepers M, Villanueva EB, Parsons MP, Xie YY, Anderson L, Felczak B, Waltl S, Ko S, Cheung D, Dal Cengio L, Slama R, Petoukhov E, Raymond LA, Hayden MR*. (2016) An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. Hum Mol Genet. 25(17):3654-3675. PMID: 27378694
    3. Kay C, Collins JA, Skotte NH, Southwell AL, Warby SC, Caron NS, Doty CN, Nguyen B, Griguoli A, Ross CJ, Squitieri F, Hayden MR. (2015) Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-Specific Silencing in Huntington Disease Patients of European Ancestry. Mol Ther. 23(11):1759-1771. PMID:26201449
    4. Southwell AL*, Smith SEP*, Davis TR, Villanueva EB, Caron NS, Xie Y, Collins JA, Sturrock A, Leavitt BR, Schrum AG, Hayden MR. (2015) Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 5:12166. PMID:26174131
    5. Mattis VB, Tom C, Saeedian J, Østergaard M, Southwell AL, Doty CN, Ornelas L, Sahabian A, Lenaeus L, Mandefro B, Sareen D, Bard J, Arjomand J, Hayden MR, Svendsen CN. (2015) HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF-withdrawal due to glutamate toxicity. Hum Mol Genet. 24(11):3257-3271. PMID:25740845
    6. Østergaard M, Thomas G, Koller E, Southwell AL, Hayden MR, Seth PP (2015) Biophysical and biological characterization of hairpin and molecular beacon RNase H active antisense oligonucleotides. ACS Chem. Biol. 10(5):1227-1233. PMID:25654188
    7. Skotte NH, Southwell AL, Østergaard M, Carroll JB, Warby SS, Doty CN, Petoukhov E, Vaid K, Kordasiewicz H, Watt AT, Freier SM, Hung G, Seth PP, C. Bennett CF, Swayze EE, Hayden MR. (2014) Allele-specific suppression of mutant huntingtin using anti-sense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS ONE. 9(9):e107434. PMID:25207939
    8. Southwell AL, Skotte NH, Kordasiewicz H, Østergaard M, Watt AT, Carroll JB, Doty CN, Villanueva EB, Petoukhov E, Vaid K, Xie Y, Freier SM, Swayze EE, Seth PP, Bennett CF, Hayden MR. (2014) In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotide drugs. Mol Ther.  22(12):2093-2106. PMID:25101598 [Featured on the cover
    9. Kolodziejczyk K, Parsons MP, Southwell AL, Hayden MR, Raymond LA. (2014) Striatal synaptic dysfunction and hippocampal plasticity deficits in the Hu97/18 mouse model of Huntington disease. PLoS ONE. 9(4):e94562. PMID:24728353
    10. Østergaard M, Southwell AL, Kordasiewicz H, Watt A, Skotte N, Doty C, Vaid K, Villanueva E, Swayze E, Bennett CF, Hayden M, Seth PP. (2013) Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant huntingtin in the CNS. Nucleic Acids Res. 1;41(21):9634-50. PMID:23963702
    11. Southwell AL, Warby SC, Carroll JB, Doty CN, Skotte NH, Zhang W, Villanueva EB, Kovalik V, Xie Y, Pouladi MA, Collins JA, Yang XW, Franciosi SF, Hayden MR. (2013) A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet. 1;22(1):18-34. PMID:23001568[In Brief:  Genetics: Fully humanized mouse model of Huntington disease. Nature Rev Neurol 8, 594 (2012)/qwe456]
    12. Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N, Hung G, Bennett CF, Freier SM, Hayden MR. (2011) Potent and selective antisense oligonucleotides targeting single nucleotide polymorphisms in the Huntington disease gene. Mol Ther. 19(12):2178-85. PMID:21971427
    13. Southwell AL, Bugg CW, Kaltenbach LS, Dunn D, Butland S, Weiss A, Paganetti P, Lo DC, Patterson PH. (2011) Perturbations with intrabodies reveal that calpain cleavage is required for degradation of huntingtin exon 1. PLoS One 6(1):e16676. PMID:21304966
    14. Southwell AL, Ko J, Patterson PH. (2009) Intrabody gene therapy ameliorates motor, cognitive and neuropathological symptoms in multiple mouse models of Huntington’s disease. J Neurosci. 29:13589-13602. PMID:19864571 [Reviewed in: March 2010 European Huntington’s Disease Network News]
    15. Southwell AL, Khoshnan A, Dunn DE, Bugg CW, Lo DC, Patterson PH. (2008) This week in the Journal: Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity. J Neurosci. 28:9013-9020. PMID:18768695 [This Week in the Journal and Reviewed in: June 2009 European Huntington’s Disease Network News]
View Full Profile
    Dr. Kiminobu Sugaya
  • Title: Professor, Neuroscience Division Leader
  • Office: BBS 412
  • Phone: 407.266.7045
  • Stem cell therapies for neurodegenerative diseases.
  • Send an Email
  • Biography:

    Our research focus is to develop stem cell therapies for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and ALS.

    We reported that human fetal neural stem cells transplanted into 24-month-old rats developed into neural cells and significantly improved the cognitive function of the animals. However, ethical and technical issues put off the clinical use of fetal or embryonic stem cell. Recently we succeeded to produce neural cells form adult human mesenchimal stem cells after modification of DNA methylation. Currently, we are investigating genes, which regulate stemness to convert committed cells into pluripotent cells. We also one-step further to extend this autologous cell therapy concept by a small molecule compound. Peripheral administrations of this compund not only dramatically (7 fold) increases endogenous neural stem cell but also neurogenesis in the aged rats.

    Investigation of stem cell biology also give us a clue for cause of disease. We found reelin, which expression is known to be reduced in schizophrenia and autism, and ?-amyloid precursor protein (APP), which produces amyloid ? depositions in Alzheimer’s disease, are involved in stem cell migration and differentiation using knockout and/or transgenic mice. Thus these factors may play an important role not only in neuroplasticity in the normal condition, but also in a deficit of adult neurogenesis under pathological conditions. Thus we are investigating novel therapeutic strategies for this disease, including modifications of stem cell and regulation of these factors.

    Using all these advanced stem cell technologies, we may be able to change therapeutic strategies for neurodegenerative diseases form delaying progress of the diseases or symptomatic treatments to the cure near future. Our researches are supported by NIH (R01 AG 23472 and R01AG20011) and Alzheimer’s Association (IIRG-03-5577).

    Recent Publications

    1. Alvarez A, Hossain M, Dantuma E, Merchant S, and Sugaya K. Nanog overexpression allows human mesenchymal stem cells to differentiate into neural cells. 2010  Neuroscience & Medicine in press

    2. Merchant S, Dantuma E, and Sugaya K: A heterocyclic pyrrolopyrimidine compound as a possible candidate for topical application to induce hair restoration. 2010 Advanced Studies in Biology; 2(2): 63-71.

    3. Field M, Bushnev S, Sugaya K.: Embryonic stem cell markers distinguishing cancer stem cells from normal human neuronal stem cell populations in malignant glioma patients. 2010 Clinical Neurosurgery in press

    4. Kwak YD, Dantuma E, Merchant S, Bushnev S, Sugaya K: Amyloid-β Precursor Protein Induces Glial Differentiation of Neural Progenitor Cells by Activation of the IL-6/gp130 Signaling Pathway. 2010 Neurotoxicity Research. in press

    5. Sugaya, K.: Stem Cell Biology in the Study of Pathological Conditions. 2010 Neurodegenerative Diseases; 7(1-3): 84-87.

    6. Chigurupati S, Venkataraman R, Barrera D, Naganathan A, Madan M, Paul L, Pattisapu JV, Kyriazis GA, Sugaya K, Bushnev S, Lathia JD, Rich JN, and Chan SL: Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. 2010 Cancer Research; 70(1): 418—27.

    7. Field, Melvin M.D.; Bushnev, Sergey M.D.; Alvarez, Angel A. B.S.; Avgeropoulos, Nicholas M.D.; Sugaya, Kimi Ph.D, Markers Distinguishing Cancer Stem Cells from Normal Human Neuronal Stem Cell Populations in Malignant Glioma Patients,Neurosurgery: August 2009 65(2)  426

    8. Biener G, Vrotsos E, Sugaya K, Dogariu A. Optical torques guiding cell motilityOpt Express. 2009 Jun 8;17(12):9724-32

    9. Vrotsos EG, Kolattukudy PE, Sugaya K. MCP-1 involvement in glial differentiation of neuroprogenitor cells through APP signaling. Brain Res Bull. 2009 Apr 29;79(2):97-103.

    10. Vrotsos EG, Sugaya K. MCP-1-induced migration of NT2 neuroprogenitor cells involving APP signaling. Cell Mol Neurobiol. 2009 May;29(3):373-81.

    11. Sugaya K, Merchant S. How to approach Alzheimer’s disease therapy using stem cell technologies. J Alzheimers Dis. 2008 Oct;15(2):241-54. Review.

    12. Keilani S, Sugaya K. Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1. BMC Dev Biol. 2008 Jul 1;8:69-75.

    13. Liu D, Hua KA, Sugaya K., A generic framework for internet-based interactive applications of high-resolution 3-D medical image data. IEEE Trans Inf Technol Biomed. 2008 Sep;12(5):618-26.

    14. Sugaya K. Mechanism of glial differentiation of neural progenitor cells by amyloid precursor protein. Neurodegener Dis. 2008;5(3-4)

    15. Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12506-11

    16. Sugaya K., Y.D. Kwak, O. Ohmitsu, A. Marutle, N.H. Greig and E. Choumrina Practical Issues in Stem Cell Therapy for Alzheimer’s Disease. Current Alzheimer Research 2007; 4(4):370-377

    17. Pulido JS, Sugaya I, Comstock J, Sugaya K. Reelin expression is upregulated following ocular tissue injury. Graefes Arch Clin Exp Ophthalmol. 2007 Jun;245(6):889-893

    For more publication information, please visit Pubmed.

View Full Profile
    Dr. Xugang Xia
  • Title: Professor
  • Office: BBS 555
  • Phone: 407.266.7154
  • Searching for genetic mutations causing neurodegenerative diseases and revealing molecular mechanisms underlying neurodegeneration in the diseases
  • Send an Email
  • Biography:

    Initially trained as a neurologist and further trained as a researcher, I have a passion for understanding and treating neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To examine disease mechanisms, we choose the rats rather than the mice as a relevant animal model to reproduce disease phenotypes observed in patients carrying a genetic mutation and we use multidisciplinary approach to reveal molecular pathways leading to neurodegeneration in disease conditions.

    The laboratory rats are chosen to express causative genetic mutations at physiological or excessive levels. Compared to laboratory mice, laboratory rats are easier for behavioral tests and for multiple samplings and thus are chosen for expressing disease-causing mutations. Our team has established a system for producing transgenic, knockin, and knockout rats by pronuclear injection of transgene DNA and CRISPR/Cas9 encoded RNA. We have created many lines of mutant rats and have deposited characterized rat lines to the RRRC rat resource and research center (www.rrrc.us) for free distribution to academic investigators.

    Disease mechanisms are examined in mutant rats for ALS. We reproduce disease phenotypes in transgenic or knockin rats expressing a disease-causing mutation and examine the effects of pathogenic mutation on gene function at a systematic level. We have unequivocally shown that overexpression of the ALS gene TPD-43 in the motor neurons or the astrocytes is sufficient to cause cell-autonomous or non-cell-autonomous neurodegeneration in a rat model. We found that motor function is partially reversible in a rat model for the ALS. Using RNA sequencing and proteomics, we are going to reveal molecular mechanisms underlying neuronal death in the disease. Meanwhile, our team is searching for genetic mutation causing a recessive form of familial ALS.

    Genetic causes are investigated for familial PD. We are collaborating with researchers worldwide to discover novel genes in which pathogenic mutations cause PD in affected families. Using mutant rats as a relevant model, we are going to examine candidate genes for the effect of a mutation on dopaminergic function at a systematic level.

    Selected Publications:

    Huang B, Wu Q, Zhou H, Huang C, and Xia XG. Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem 2016;139 (2):285-293.

     

    Wu Q, Liu M, Huang C, Liu X, Huang B, Li N, Zhou H, Xia XG. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 2015, 129 (3): 417-428

     

    Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia XG, and Zhou H. Reactive Astrocytes Secrete LCN2 to Promote Neuron Death. Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (10): 4069-4074

     

    Tong J, Huang C, Bi F, Wu Q, Huang B, Liu X, Li F, Zhou H, Xia XG. Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 2013; 32 (13): 1917-1926

     

    Huang C, Tong J, Bi F, Zhou H, Xia XG. Mutant TDP-43 in Motor Neurons Promotes the Onset and Progression of ALS in Rats. The Journal of Clinical Investigation 2012, 122 (1): 107-118.

     

    Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H, Xia XG. Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Human Molecular Genetics 2012, 21 (21): 4602-4614.

     

    Huang C, Zhou H, Tong J, Chen H, Wang D, Wei X, and Xia XG. FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. PLoS Genet 2011, 7(3): e1002011.

     

    Zhou H, Huang C, Tong JB, and Xia XG. Early Exposure to Paraquat Sensitizes Dopaminergic Neurons to Subsequent Silencing of PINK1 Gene Expression in Mice. Int J Biol Sci 2011, 7 (8): 1180-1187.

     

    Zhou H, Huang C, Tong J, Hong WC, Liu YJ, and Xia XG. Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake. Int J Biol Sci 2011, 7 (6): 753-761.

     

    Tian T, Huang C, Yang M, Tong J, Zhou H, and Xia XG. TDP-43 potentiates α-synuclein toxicity to dopaminergic neurons in transgenic mice. Int J Biol Sci 2011, 7: 234-243.

     

    Zhou H, Huang C, Chen H, Wang D, Landel C, Xia PY, Bowser R, Liu YJ, Xia XG. Transgenic Rat Model of Neurodegeneration Caused by Mutation in the TDP Gene, PLOS Genetics 2010, Mar 26;6(3): e1000887

     

    Zhou H, Huang C, and Xia XG. A tightly regulated pol III promoter for synthesis of miRNA genes in tandem, Biochim Biophys Acta 2008, 1779: 773-779

     

    Zhou H, Falkenburger BH, Schulz JB, Tieu K, Xu Z, and Xia XG. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 2007, 3(4): 242-50.

     

    Xia XG, Zhou H, Samper E, Melov S, Xu Z. Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice. PLoS Genet 2006; 2(1): e10.

     

    Xia XG, Zhou H, Huang Y, Xu Z. Allele-specific RNAi Selectively Silences Mutant SOD1 and Achieves Significant Therapeutic Benefit in vivo. Neurobiol Dis 2006; 23(3): 578-86.

     

    Zhou H, Xia XG, Xu Z. An optimized RNA polymerase II construct for synthesis of short hairpin RNA and gene silencing. Nucleic Acids Research 2005; 33(6): e62.

     

    Xia XG, Zhou H, Zhou S, Yu Y, Xu Z. An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. J Neurochem 2005; 92: 362–367.

     

    Xia XG, Harding T, Weller M, Bieneman A, Uney JB and Schulz JB. Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 2001, 98: 10433-8.

     

    Xia XG, Schmidt N, Teismann P, Ferger B and Schulz JB. Reconstitution of striatal malonate toxicity in 6-OHDA lesioned animals by dopamine and D2 but not by D1 agonists. J Neurochem 2001, 279: 63-70.

View Full Profile
    Dr. Hongxia Zhou
  • Title: Associate Professor
  • Office: BBS 554
  • Phone: 407.266-7153
  • Devoted to reveal the causes and identify the treatments for neurodegenerative diseases including amyotrophic lateral sclerosis (ALS).
  • Send an Email
  • Biography:

    My research projects are funded by multiple NIH grants (R01NS073829 and R01NS089701). The projects are designed to study the molecular mechanisms underlying neurodegeneration in ALS and in the other neurodegenerative diseases. Using advanced genetic tools, we have created novel transgenic and knockin rats as relevant models for in vivo study on neurodegeneration.

    1). Neurodegeneration in ALS is partially reversible in a rat model. Using a tetracycline-inducible gene expression system, we examined the reversibility of neurodegeneration in an ALS model. We found that neurons are prevented from demise in paralyzed rats after the ALS-causing gene TDP-43 is stopped from further expression. Motor function is partially recovered in the rats due to functional compensation from survived neurons. As no effective treatment is currently available for ALS, our finding will encourage every effort to search for therapeutic treatments for the disease.

    2). Reactive astrocytes secrete neurotoxic factors such as LCN2 to promote neuron death in neurodegenerative diseases. Astrocytes often become reactive in neurodegenerative diseases and reactive astrocytes are believed to be harmful to neurons. How reactive astrocytes exert a toxicity on neurons is not clear. We used comprehensive approach in search of potent molecules mediating astrocytic neurotoxicity. We identified that reactive astrocytes secrete lipocalin 2 (LCN2) as a potent mediator of astrocytic neurotoxicity. LCN2 is known to stimulate quiescent astrocytes and microglia to become reactive. Caution must be taken when glial replacement is tested for therapeutic effects against neurological diseases.

    3). Multiple lines of mutant rats are created for studying the mechanisms of neurodegeneration. We have created many mutant rats which express human disease genes and develop disease-reminiscent phenotypes. We have deposited these novel rats to RRRC rat resource and research center (www.rrrc.us) for free distribution to academic investigators.

    Along with my long-term collaborator Dr. Xugang Xia, I am leading my research team to reveal disease mechanisms and identify effective treatment for neurodegenerative diseases.

    Recent Publications:

    Huang B, Wu Q, Zhou H, Huang C, and Xia XG. Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem 2016;139 (2):285-293.

    Wu Q, Liu M, Huang C, Liu X, Huang B, Li N, Zhou H (corresponding author), Xia XG. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 2015, 129 (3): 417-428

    Huang C, Huang B, Bi F, Yan LH, Tong J, Huang J, Xia XG, Zhou H. Profiling the genes affected by pathogenic TDP-43 in astrocytes. J Neurochem 2014; 129 (6):932-9.

    Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia XG, and Zhou H. Reactive Astrocytes Secrete LCN2 to Promote Neuron Death. Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (10): 4069-4074

    Tong J, Huang C, Bi F, Wu Q, Huang B, Liu X, Li F, Zhou H (corresponding author), Xia XG. Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 2013; 32 (13): 1917-1926

    Huang C, Tong J, Bi F, Zhou H (corresponding author), Xia XG. Mutant TDP-43 in Motor Neurons Promotes the Onset and Progression of ALS in Rats. The Journal of Clinical Investigation 2012, 122 (1): 107-118.

    Tong J, Huang C, Bi F, Wu Q, Huang B, Zhou H. XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats. Journal of Neurochemistry 2012, 123 (3): 406-416.

    Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H (corresponding author), Xia XG. Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Human Molecular Genetics 2012, 21 (21): 4602-4614.

    Huang C, Zhou H (corresponding author), Tong J, Chen H, Wang D, Wei X, and Xia XG. FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. PLoS Genet 2011, 7(3): e1002011.

    Zhou H (corresponding author), Huang C, Tong JB, and Xia XG. Early Exposure to Paraquat Sensitizes Dopaminergic Neurons to Subsequent Silencing of PINK1 Gene Expression in Mice. Int J Biol Sci 2011, 7 (8): 1180-1187.

    Zhou H (corresponding author), Huang C, Tong J, Hong WC, Liu YJ, and Xia XG. Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake. Int J Biol Sci 2011, 7 (6): 753-761.

    Tian T, Huang C, Yang M, Tong J, Zhou H (corresponding author), and Xia XG. TDP-43 potentiates α-synuclein toxicity to dopaminergic neurons in transgenic mice. Int J Biol Sci 2011, 7: 234-243.

    Huang C, Xia PY, Zhou H. Sustained expression of TDP-43 and FUS in motor neurons in rodent’s lifetime, Int J Biol Sci 2010, 4: 396-406

    Zhou H (Corresponding author), Huang C, Chen H, Wang D, Landel C, Xia PY, Bowser R, Liu YJ, Xia XG. Transgenic Rat Model of Neurodegeneration Caused by Mutation in the TDP Gene, PLOS Genetics 2010, Mar 26;6(3): e1000887

    Zhou H, Huang C, Yang M, Landel CP, Xia PY, Liu YJ, and Xia XG. Developing tTA transgenic rats for inducible and reversible gene expression. Int J Biol Sci 2009, 2: 171-181

    Wu R, Wang H, Xia XG, Zhou H, Liu C, Castro MG, and Xu Z. Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS. Antioxid Redox Signal 2009, 11: 1523-1534

    Zhou H, Huang C, and Xia XG. A tightly regulated pol III promoter for synthesis of miRNA genes in tandem, Biochim Biophys Acta 2008, 1779: 773-779

    Wang H, Ghosh A, Baigude H, Yang CS, Qiu L, Xia X, Zhou H, Rana TM, and Xu Z. Therapeutic gene silencing delivered by a chemically modified small interfering rna against mutant sod1 slows amyotrophic lateral sclerosis progression, J Biol Chem 2008, 283: 15845-15852

    Qiu L, Wang H, Xia X, Zhou H, and Xu Z. A construct with fluorescent indicators for conditional expression of mirna, BMC Biotechnol 2008, 8:77

    Zhou H, Falkenburger BH, Schulz JB, Tieu K, Xu Z, and Xia XG. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 2007, 3(4): 242-50.

    Xia XG, Zhou H (co-first author), Samper E, Melov S, Xu Z. Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice. PLoS Genet 2006; 2(1): e10.

    Xia XG, Zhou H, Huang Y, Xu Z. Allele-specific RNAi Selectively Silences Mutant SOD1 and Achieves Significant Therapeutic Benefit in vivo. Neurobiol Dis 2006; 23(3): 578-86.

    Zhou H, Xia XG, Xu Z. An optimized RNA polymerase II construct for synthesis of short hairpin RNA and gene silencing. Nucleic Acids Research 2005; 33(6): e62.

    Xia XG, Zhou H, Zhou S, Yu Y, Xu Z. An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. J Neurochem 2005; 92: 362–367.

    Trendelenburg AU, Gomeza J, Klebroff W, Zhou H, Wess J. Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter release: a study with M2- and M4-receptor-deficient mice. Br J Pharmacol 2003; 138: 469-480.

    Zhou H, Meyer A, Starke K, Trendelenburg AU. Heterogeneity of release-inhibiting muscarinic autoreceptors in heart atria and urinary bladder: a study with M2– and M4-receptor-deficient mice. Naunyn-Schmiedeberg’s Arch Pharmacol 2002; 365:112-122.

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