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Fellowship Mentors

Detlef Heck, PhD
Research Interest: The research project will use automatic video tracking technology for a detailed quantitative investigation of social and motor behavior in normal mice and mouse models of heritable brain disorders (autism and ataxia). The goal is to identify quantifiable deficits in complex social and simple motor behaviors in mouse models of human brain disorders. The project involves the handling of mice, performance of behavioral tests, recording of the video data and analysis of the data using statistical analysis software packages (Sigmastat, SPSS or SAS). All activities will be performed in under the supervision of the PI (Dr. Heck).

Max Fletcher, PhD
Research Interest: My research focuses on understanding the basic principles of neural encoding of sensory information and how both experience and learning can affect this process. Specifically, my work has focused on investigating how simple forms of learning can enhance sensory processing in the early stages of the olfactory pathway and lead to changes in perception. To accomplish this, I have employed a broad range of techniques including in vivo electrophysiology, awake and anesthetized in vivo imaging, in vivo two-photon calcium imaging, and as well as behavioral approaches.

Kristin Hamre, PhD
Research Interest: Depending upon the interest of the student, there are two possible types of techniques that a student could learn. One is that the student could learn about behavioral testing of mice to examine both baseline and alcohol-mediated behaviors that measure such parameters as anxiety and balance/ coordination.  Second, through the analysis of development a student could learn techniques such as genotyping through the use of PCR and histological processing of tissue.

Marcia Honig, PhD
Research Interest: The research in my laboratory is focused on examining the behavioral consequences of traumatic brain injury (TBI) and the associated pathological changes, through the use of a mouse model.  We create the injury by delivering a high-pressure air blast to a restricted part of one side of the cranium, after anesthetizing and stabilizing the mouse to restrict its movement and shielding the rest of the head and the entire body from the blast.  In terms of the biomechanical forces produced by the air blast, the functional deficits exhibited by the mice, and the widespread axonal injury later observed with histological analysis, our model very much mimics the mild TBI (i.e. concussion) sustained by humans during traumatic incidents such as sports injuries, motor vehicle accidents, and falls, where the skull remains intact.  Accompanying the initial axonal injury, microglia become activated and the ensuing neuroinflammation contributes to further pathogenesis.

We are currently pursuing this in two ways.  First, we are utilizing a pharmacological agent that modulates microglia in such a way as to improve the outcome from TBI, and may also provide benefit in neurodegenerative diseases such as Alzheimer’s and ALS where neuroinflammation contributes to disease progression.  Secondly, we are examining how neuroinflammatory responses contribute to long-term decline, particularly with regard to cognitive function and following multiple traumatic events.

Tauheed Ishrat, PhD
Research Interest: The broad goal of our lab is to understand, at a cellular and molecular level, the interplay between inflammation and oxidative stress in neurovascular injury after stroke, and to develop novel therapeutic strategies. We integrate cellular, molecular, genetic, and pharmacological approaches to elucidate the mechanisms that control the progression of neurovascular brain injury after stroke.

Stroke is a major cause of long-term disability worldwide and there is no treatment for it except recombinant tissue type plasminogen activator (rtPA). rtPA can be administered only within a short time window (4.5 hours) after stroke onset, and it often leads to rupturing of the cerebrovascular system, leading to hemorrhage, oxidative stress and inflammation. We believe that treatment of acute stroke with rtPA in combination with certain potent neuroprotectants/ small molecules can combat oxidative stress and inflammation and will prove to be a good strategy to prevent secondary injury.

Our laboratory uses a multidisciplinary approach to examine the molecular mechanisms and therapeutic targets involving in neurovascular injury including, Western blotting, PCR, immunocytochemistry, and cutting edge neuroscience techniques. In addition, we incorporate a broad variety of functional behavioral tests useful for investigating experimental manipulations including, the Morris water maze, Beam walk open field apparatus, passive avoidance, CatWalk, rotarod apparatus, and Grip strength test, Novel Object recognition.

Tony Reiner, PhD
Research Interest: The work in our laboratory focuses on the organization, function, and diseases of the basal ganglia and eye. We have also recently begun to develop a mouse model of traumatic brain injury, to develop treatments for the adverse outcomes from traumatic brain injury. Finally, we also have a longstanding interest in the evolution and fundamental organization of the vertebrate forebrain.

With respect to basal ganglia, we are characterizing the synaptic organization of the thalamic and cortical inputs to the striatum, to better understand the neuronal functional circuitry that underlies the role of the basal ganglia in movement control. In our approach, we use neuron type selective labeling methods (immunolabeling, tracer injection, or single-cell filling, engineered mouse lines) to define the inputs to specific basal ganglia cell types from specific cortical and thalamic neuron types using high resolution LM and EM imaging. We have found that the direct pathway neurons of the striatal part of the basal ganglia, that mediate movement initiation and execution, receive their cortical input from neurons involved in pre-motor planning. By contrast, indirect pathway neurons of the striatum receive their major cortical input from corticospinal neurons that directly effect movement. In future studies, we plan to genetically disable one or the other of these cortical inputs to better understand their individual contributions to motor learning and motor function.

In our work on basal ganglia disease, we study the means by which the gene mutation in Huntington's disease (HD) leads to selective destruction of neurons in the striatal part of the basal ganglia. We use genetically engineered mice, and we have been particularly interested in the role that perturbed function of cortical neurons projecting to striatum plays in injuring their target striatal neurons. This injury process could involve excess glutamate release from corticostriatal terminals or diminished production by corticostriatal neurons of the neurotrophic factor BDNF, which is needed for survival by striatal neurons. Based on this premise, we examined and demonstrated the efficacy of an mGluR2/3 agonist in ameliorating symptoms in a mouse model of HD. This drug both diminishes corticostriatal glutamate release and enhances BDNF delivery to striatum. We plan to further test efficacy of this drug class in more genetically and phenotypically precise mouse HD models.

In our work on the visual system, we study the neural mechanisms by which blood flow in the choroid of the eye is adaptively controlled according to retinal need, and in the role disturbances in such neural control may play in age-related decline in retinal function. We are currently studying the autonomic mechanisms linking systemic and ocular blood flow that maintain the needed levels of blood flow to the retina. We are examining the possibility that disruption of such neural control of ocular blood flow predisposes it to the inflammatory injury cascade that causes outer retinal injury in age-related macular degeneration.

In our work on traumatic brain injury (TBI), we have been developing a novel closed-head air blast model in mice. We have identified a range of blast pressures that mimic human TBI in that they yield diffuse axonal injury to brain, motor impairments, and anxiety disorder resembling post-traumatic stress disorder (PTSD). We are testing treatments that improve recovery from TBI, especially the PTSD outcome, and we plan to characterize the molecular mechanisms and genetic susceptibilities underlying TBI.

Finally, we have a longstanding interest in the evolution of the cerebral cortex, basal ganglia, and thalamus, and in how these structures differ among birds, reptiles and mammals. In our studies, we use neurochemistry, hodology and the localization of developmentally regulated genes to characterize the organization of these regions, and ascertain the course evolution has taken to fashion the very different appearing brains of birds and mammals.

Michael P. McDonald, PhD
Research Interest: Our lab studies the involvement of gangliosides in the behavioral and cognitive impairments, protein misfolding, and neurodegeneration of Alzheimer's and Parkinson's diseases. Gangliosides are glycolipids richly expressed in neuronal membranes. Although the functions of gangliosides are not completely understood, converging evidence clearly demonstrates a critical role for membrane gangliosides in the binding and aggregation of amyloid-β (Aβ), the toxic peptide that aggregates into plaques in Alzheimer's disease. Our previous research showed that elimination of the GD3 synthase (GD3S) gene significantly reduces Aβ binding and Aβ -induced cell death in primary neuronal cultures. In a mutant mouse model of Alzheimer's disease, knocking out GD3S nearly eliminates plaque formation and Aβ -associated neuropathology, and reverses memory deficits. Because GD3 ganglioside is a critical mediator of the ceramide-sphingomyelin-mediated apoptotic pathway, we expect that inhibiting GD3S will also be neuroprotective in models of Parkinson's disease. In addition to targeted mutation of GD3S, ongoing experiments involve injection of viral-vector-mediated small-interfering RNA (siRNA) constructs to "silence" GD3S, and intracranial infusion of v. cholerae sialidase (VCS), an enzyme that hydrolyzes specific sialic acid residues on gangliosides. Both of these manipulations have the effect of reducing levels of the more-complex brain gangliosides, which have a high affinity for Aβ, and increasing levels of the less-complex brain gangliosides, which have a lower affinity for Aβ and are neuroprotective. We expect this line of research to provide insight into new therapeutic targets for Alzheimer's and Parkinson's diseases.

Lawrence T. Reiter, PhD
Research Interest: My laboratory utilizes the powerful genetic model organism Drosophila melanogaster (fruit flies) to investigate the functions of genes involved in human neurological diseases. Our main focus is the study of genes related to Angelman syndrome and autism spectrum disorders. These disorders are interrelated at the molecular level and one of the goals of our laboratory is to identify genes and proteins regulated by one or more of the proteins that can cause and autism phenotype. In addition, approximately 3-5 % of all autism cases result from maternally derived duplications of the region containing the gene that causes AS, UBE3A. Mutations in the protein targets of the ubiquitin ligase UBE3A may therefore account for a significant percentage of idiopathic autism cases as well.

In our laboratory we utilize Drosophila specific genetic techniques that allow us to generate artificially high levels of normal and mutant fly Dube3a proteins in fly heads. Wild type, dominant negative and epitope tagged forms of ube3a are over-expressed in the brains of flies using the GAL4/UAS system in order to increase or decrease the levels of Dube3a protein targets. We have now identified 50 of these potential Dube3a regulated proteins (Jensen et al. PLoS One. 2013 Apr 23;8(4):e61952) and are actively validating these interactions using whole genome molecular methods (genomics), genetic suppressor/enhancer screens, immunostaining in fly neurons (immunoflourescence), and changes in synaptic function and stability at the fly neuromuscular junction (electrophysiology). Using these methodologies in flies we have identified Dube3a regulation of the actin cytoskeleton (Reiter et al. Hum Mol Genet. 2006 Sep 15;15(18):2825-35) as well as the synthesis of monoamines (Ferdousy et al. Neurobiol Dis. 2011 Mar;41(3):669-77) and ion transport across axonal membranes (Jensen et al. PLoS One. 2013 Apr 23;8(4):e61952).

We have also been doing in depth phenotypic and molecular analysis of individuals with interstitial duplication 15q autism. Since 2007 we have been collecting a variety of language, neuropsychiatric, neurological and gene expression data from subjects with interstitial 15q chromosomal duplications and just recently published our clinical findings (Urraca et al. 2013 Autism Res. 2013 Aug;6(4):268-79). We hope that our basic research into the functional targets of UBE3A will lead to a better understanding of the phenotypes in this particular autism population where the UBE3A gene is duplicated, and presumably expressed at higher levels than in unaffected individuals. For more information on our clinical study see http://www.dup15q.org/events/scientific-conferences/2015-scientific-meeting/larry-reiter-2015/. As an extension of this work which bridges the gap between basic and clinical research, we recently began an NIH funded study to generate dental pulp derived neurons from individuals with either the Angelman syndrome deletion in this region or a duplication of this region on chromosome 15q causing autism. We hope that these patient-derive neuronal cultures will allow us to perform more in depth molecular and electrophysiological analysis of both conditions in the near future. For more information on the dental pulp stem cell study please see http://tinyurl.com/88f688l.

Monica Jablonski, PhD
Research Interest: Mechanisms that regulate photoreceptor outer segment assembly; mouse models of eye disease; proteomics; retinal cell biology; mutagenesis; genetics modulators of glaucoma

Abbas Babajani-Feremi, PhD
Research Interest: Signal and image processing, Medical imaging, Brain connectivity analysis, Functional magnetic resonance imaging (fMRI), Magnetoencephalography (MEG) and electroencephalography (EEG), Electrocorticography (ECoG) (or intracranial EEG (iEEG)), Transcranial magnetic stimulation (TMS), Dynamic contrast enhancement MRI (DCE-MRI), Epilepsy, Alzheimer’s disease, sleep disorder, and traumatic brain injury (TBI)

Shalini Narayana, PhD
Research Interest: My research is centered on two main areas: 1. Optimizing the clinical application of non-invasive brain imaging and stimulation methods in diagnostic and therapeutic domains, and 2. Characterizing functional characterization of the speech and limb motor networks and disease, injury, and treatment induced plasticity in these systems. These research objectives are focused around human speech and motor systems and use multimodal neurophysiological imaging methods. The neuroimaging methods used include magnetoencephalography (MEG), Transcranial magnetic stimulation (TMS), and functional magnetic resonance imaging (fMRI).

Ongoing research projects include examining the therapeutic effects of TMS in speech and voice disorders in Parkinson's disease, and epilepsy. Other studies include developing population normative data of TMS derived neurophysiological parameters and optimizing non-invasive brain stimulation and functional imaging in the context of presurgical mapping.

The lab is also investigating functional connectivity of speech and limb motor systems. Studies are also characterizing changes in the speech motor system resulting from Parkinson's disease and the compensatory adaptations in the network following voice treatment as well as identifying neurophysiological correlates of performance enhancement resulting from motor training and adjuvant TMS.

Jianxiong Jiang, PhD
Research interest: The research in our laboratory is primarily dedicated to a better understanding of neuroinflammatory processes following brain insults such as prolonged seizures. We have also recently begun to explore the neuron-glia interactions in malignant gliomas, the most devastating brain tumors that constitute a major cause for epilepsy, particularly in the elderly. We attempt to unlock the cellular and molecular mechanisms whereby normal brains are transformed to generate spontaneous recurrent seizures, i.e., acquired epileptogenesis. We are also interested in developing novel antiepileptic and/or antiepileptogenic therapeutics in close collaboration with medicinal chemistry laboratories. To achieve these goals, we use a variety of technologies and experimental systems, such as high-throughput screening, chemical genetics, TR-FRET, RNAi, CRISPR/Cas9, microdialysis, time-locked video EEG, behavioral tests, etc.
Anna Bukiya, PhD

Research Interest: The major line of interest in the lab is the lipid regulation of alcohol effect on cerebral circulation at different points during lifetime (from in utero into late adulthood). We are currently pursuing several lines. We are studying the role of dietary cholesterol in the physiology and pathology of cerebral arteries via ion channel involvement. Using rat model of high-cholesterol diet, we were the first to show that dietary cholesterol was a critical nutritional regulator of alcohol-induced constriction of cerebral arteries. After establishing the phenomenon at organ level, we are currently dissecting out molecular and structural mechanisms that enable cholesterol regulation of alcohol-induced constriction of cerebral arteries. Considering that statins - cholesterol lowering therapy - are one of the most widely prescribed and consumed drugs, we are studying their effect on cholesterol level in cerebral artery tissue and on artery response to alcohol.

Another line of work is carried out in close collaboration with the Department of Comparative Medicine and with the Department of Obstetrics and Gynecology at UTHSC. This line of work involves non-human primates - baboons, whose pregnancy and developmental milestones are similar to humans. We are focused on the role of endocannabinoid lipids in alcohol effect on fetal cerebral circulation during maternal binge drinking. We are aiming at identification of novel targets of maternal drinking in fetal cerebral arteries. This exploratory work may lay a foundation to early diagnostics and successful prevention/treatment of the fetal alcohol spectrum disorders (FASD) and fetal alcohol syndrome (FAS) that are estimated to affect at least 1% of births in the USA.

In addition, we are working on the interaction of potassium (e.g. GIRK, BK) channels with physiologically relevant lipids. In close collaboration with Dr. Alex Dopico (UTHSC), we were able to map several lipid-sensing sites in both BK channel-forming and accessory beta 1 subunits. These studies include recognition motifs for bile acids, cholesterol, and leukotriene B4. We are currently working on developing synthetic ligands for these sites. Newly discovered ligands will be used as lead compounds for designing drugs that modulate diameter of cerebral arteries via action on BK channel. In another collaborative line with Dr. Avia Rosenhouse-Dantsker at the University of Illinois at Chicago we are studying molecular mechanisms of cholesterol modulation of GIRK channels and potential implications of such modulation on GIRK channel physiology and role in Down syndrome pathology.

Hao Chen, PhD
Research Interest: My long-term interest is to elucidate the complex interaction between social, genetic, and sensory factors in regulating drug abuse behavior, particularly cigarette smoking and alcohol drinking, by using rodent models. Behavioral, anatomical, molecular, genetic, genomic and informatics approaches are integrated to investigate the mechanisms underlying the effects of social and genetic factors on drug abuse and addiction behavior.

Alex Dopico, MD, PhD
Research Interest: My laboratory is interested in determining the mechanism of action of small amphiphilic compounds on ion channels from excitable cells. One of these amphiphiles is alcohol, the most widely used and abused drug. Some others are physiological modulators, such as bile acids and neurosteroids. Our current research is focused on two projects dealing with large conductance, Ca++-activated K+ (BK) channels. These channel proteins have been demonstrated to be involved in both controlling central neuron excitability and regulating arterial smooth muscle tone. Project 1: To determine the molecular basis for differential actions of alcohol on BK channels from mammalian brain vs. arterial smooth muscle, including modulation of drug action by membrane lipids. Project 2: To determine the structural requirements (both in the amphiphile molecule and the ion channel protein) for the modulation of arterial muscle BK channels by bile acids.

For these studies we combine electrophysiological and molecular biology techniques. Ion channel responses to drug exposure are evaluated in: 1) freshly isolated cells, where we study drug modification of channel behavior in the native environment of the channel protein; 2) isolated patches of cell membrane, where we can address the differential role of different membrane-bound vs. cytosolic second messengers in drug action; 3) artificial bilayers of controlled lipid composition, where we can determine the modulatory role of membrane lipids in drug action.

Ion channel isoforms from relevant tissue are identified. Following mRNA isolation and cloning, channel subunits of known sequence are expressed in heterologous systems such as Xenopus oocytes or HEK-293 cells. Then, we can determine the role of channel subunit composition in drug action by studying drug effects on ion channel complexes that differ in pore-forming and/or modulatory subunit composition. In addition, differential responses to a drug by channels that differ in a given region of a subunit, when studied in the same proteolipid environment, allow us to postulate sites in that subunit for drug recognition. This is probed by studying drug action on expressed channel proteins that include mutations in the postulated region(s).

My laboratory is interested in determining the molecular mechanism of action of alcohol and other small amphiphiles on ion channel proteins from the brain and arterial vessels. To determine the recognition sites for alcohol in these proteins and how alcohol modifies protein function upon interaction with these sites, will provide critical information for understanding how the drug interacts with its targets and, eventually, lead to the design of clinically useful agents to treat conditions associated with alcohol intake.

Changhoon Jee, PhD
Research interest: My research is focusing on understanding how animals modulate innate state of motivation and make a risky-decision to develop compulsive behaviors that have pivotal role in the development of Substance abuse Disorders (SUD) and comorbid neuropsychiatric disorders.

I exploit sophisticated behavioral paradigms in the simplest and most completely defined connectome using C. elegans. C. elegans exhibit state dependent development of chemical preference, which is analogous to studies in mammalian models and has been shown to be a powerful and deployable genetic tool to study alcohol and drug dependence. To model decision-making regarding motivational state, we investigate two distinct motivated behaviors against aversive stimuli: 1) male copulation behavior, pursuing natural reward such as sexual drive, against aversive blue light irritant, 2) ethanol seeking, which hijacked brain reinforcement circuits in mammals, over the aversive chemical barrier respectively, and 3) other psychostimulant-dependent behaviors (nicotine, amphetamine).  

Our laboratory is working on neuropeptidergic regulation of compulsive behaviors including corticotropin-releasing factor (CRF) receptor ortholog GPCR in C. elegans, enhance motivational state resulted in compulsive engagement in innate drive using genetic manipulations, microsurgeries, electrophysiological recordings, and optogenetic tool. Additionally, we are pursuing to establish a solid base for developing novel chemical agents for advanced treatment of Anxiety Disorders and Substance abuse Disorders (SUD) by phenotypic screening.

Kafait U. Malik, PhD, DSc
Research Interest: The overall objective of our research is to elucidate the cellular and molecular signal transduction mechanisms of growth factors, circulating hormones including angiotensin II (Ang II) and locally generated autacoids (eicosanoids) and adrenergic transmitter norepinephrine (NE) in the regulation of cardiovascular function in health and in the development of hypertension and vasculopathy associated with restenosis, atherosclerosis and diabetes.   Our studies should further our knowledge of the neuro-humoral mechanisms that regulate vascular function and its alteration in vascular diseases.  Moreover, these studies should allow formulating rational approaches for the development of novel therapeutic agents for the treatment of hypertension, arteriosclerosis and restenosis.

We use isolated cultured vascular smooth muscle and endothelial cells, isolated perfused organs (heart, kidney and blood vessels), wire myograph for measuring vascular reactivity models of hypertension (Ang II- and DOCA-Salt and SHR), balloon injured carotid artery and now we are also transgenic animals for our studies. The laboratory techniques also include the use of HPLC-GC-Mass spectrometric Analysis of Eicosanoids, SDA-PAGE and Western blot analysis, DNA and RNA isolation, purification and quantitation, PCR, RT-PCR, Q-PCR, DNA transfection in cells Plasmid preparation, restriction fragment mapping, Construction of siRNA of various signal molecules, Transfection of reporter vectors as well as over-expression of constitutively active or dominant negative proteins, Co-immunoprecipitation and co-localization techniques, con-focal microscopy, site direct mutagenesis Molecular imaging of protein interactions Immunoassays and protein analysis, insertion of miRNA into adeno-, lenti- and adeno-associated viral vectors and preparation of viruses for transfection in cultured cells and for in vivo use. The signaling molecules studied by ELISA, in vitro kinase assay and Proteomics include, RasGTPas, ERK1/2, MEK, Raf, p38MAPK, c-JNK, PI3 kinase, Akt, JAK-STA, Pyk-2, c-Src, Syk and EGF.

Kazuko Sakata, PhD
Research Interest: Current projects in my laboratory focus on studying the roles of gene regulation of brain-derived neurotrophic factor (BDNF) in major depression. BDNF is a major neuronal growth factor in the brain that promotes neuronal development and synaptic plasticity. BDNF has been suggested to be involved in both pathophysiology of depression and action of antidepressants; BDNF expression is decreased in the serum, hippocampus and prefrontal cortex (PFC) of patients with major depression, which can be reversed by chronic, but not acute, antidepressant treatments. However, the underlying mechanisms of how decreased BDNF levels lead to depression and of how increased BDNF levels provide antidepressant effects remain to be understood. We are trying to address these underlying mechanisms by focusing on BDNF promoters using promoter specific mutant mice. Our research goal is to find out how promoter-specific gene regulation of BDNF is involved in pathogenesis of depression/depression-like behavior and recovery from mood disorders. We use a multidisciplinary approach from gene to behavior with genetic, molecular and biochemical, electrophysiological, and behavioral techniques. While major depression is the leading disease burden in industrialized countries including the North America, we believe that understanding the underlying mechanisms will advance the future therapy for depression.

Thirumalini Vaithianathan, PhD
Research interest: Synapses are communication points of neurons. Synaptic vesicle fusion is a tightly controlled process governed by many factors and triggered by localized calcium levels, Sensory synapses face additional challenges besides to the basic requirements, that is to be able to transmit extremely fast, precise and sustained neurotransmission that is critical for the perception of complex senses such as vision and hearing. The main objective of the research in my laboratory is to understand how retinal bipolar cells, a class of neuron critical to support both fast transient and slow sustained release are specialized for these tasks. This work study the components involved in synaptic vesicle trafficking and localized presynaptic calcium signaling in normal and degenerative disease utilizing state-of-the-art imaging, electrophysiological, electron microscopy, and pharmacological tools in retinal bipolar neurons from transgenic zebrafish and mouse models.

Fu-Ming Zhou, PhD
Research Interest: Dr. Zhou currently conducts a multidisciplinary research program designed to determine the molecular, cellular and neuropharmacological mechanisms of the brain monoamine systems. Particular attention is being paid to the contributions of these monoamine systems to neuropsychiatric disorders such as Parkinson’s disease, depression, schizophrenia, drug abuse, and attention deficit hyperactivity disorder (ADHD). We use rodents as our experimental animals. Mutant mice are also used.

Several techniques are used in the laboratory:

  • Electrophysiology-patch clamp
  • Single cell RT-PCR (in combination with patch clamp)
  • Electrochemistry (fast cyclic voltammetry at the carbon fiber microelectrode; HPLC)
  • Immunohistochemistry

Dr. Zhou's research is funded by R01 grants from the National Institute on Drug Abuse and National Institute of Mental Health and grants from private foundations.

Ioannis Dragatsis, PhD
Research Interest:

Project 1 Title: Analysis of a mouse model for Familial Dysautonomia

Familial Dysautonomia (FD) is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population, leading to death before the age of 40. The disease is characterized by progressive degeneration of the sensory and autonomic nervous system. Despite the identification of the gene that causes FD (Ikbkap) and recent medical advances, no cure is available. We have generated a mouse model recapitulating the phenotypic features of the disease and our goal is to elucidate the mechanisms that lead to neuronal degeneration in FD and to test therapeutic strategies.

Project 2 Title: Analysis of the function(s) of huntingtin

Huntington's disease (HD) is an autosomal dominant disorder that affects 1 in 10,000 individuals. HD is characterized by chorea, rigidity and progressive dementia. Symptoms usually begin between the ages of 35 and 50 years, with death typically following 15 to 20 years later. HD is caused by the expansion of an unstable stretch of CAG triplet repeats within the coding region of the HD gene. Moreover the protein encoded by the HD gene, huntingtin, is a novel protein of unknown function.

We are using the mouse as a model organism. Inactivation of the mouse homologue of the HD gene results in embryonic lethality demonstrating that huntingtin is essential for early embryonic development. Conditional inactivation of the gene at later stages results in progressive neurodegeneration in the adult mouse, suggesting that huntingtin is also essential for neuronal survival.

Valerie Vasquez, PhD
Research Interest: Mechanosensitive ion channels translate mechanical stimuli into an electrochemical signal, which ultimately leads to physiological or perceptual responses. Some of these responses in humans include touch, pain, proprioception, hearing, and blood pressure regulation. These channels do not share a common topology and so far five classes of membrane proteins have been proposed to form mechanosensitive channels in eukaryotes: the amiloride-sensitive sodium channels (DEG/ENaCs), the transient receptor potential channels (TRPs), the two-pore domain K+ channels (K2Ps), the Piezo proteins, and the transmembrane channel-like proteins (TMCs). We are particularly interested on identifying membrane lipids that regulate channel function in vivo and the mechanism by which they interact to give rise to mechano-dependent gating.

Our lab aims to understand the functional, structural, and molecular mechanism by which mechanosensitive channels respond to mechanical stimuli and help delineate a general framework for their roles in health and disease. We follow two main avenues: 1) in vitro biochemical and biophysical approaches to study protein-protein and protein-lipid interactions of bona fide mechanosensitive channel complexes, and 2) in vivo approaches to characterize mechanosensitive channels in C. elegans having novel physiological roles.

Last Published: Dec 20, 2019