Research Opportunities at UT

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Students interested in conducting research during the summer or academic year at the University of Tennessee Health Science Center may download an application form (DOC) and an evaluation form (DOC). Consult the list below of UT faculty who have expressed an interest in sponsoring Rhodes students. 

Please do not contact these faculty directly, but follow the procedures outlined in the application form. Contact Dr. Gary Lindquester for further information regarding course credit, summer support, and application procedures.

Students interested in a research in neuroscience may also apply for fellowship support at the following site: Rhodes/UT Neuroscience Research Fellowship.

The University of Tennessee Health Science Center also hosts its own Summer Undergraduate Research Fellowship (SURF) program.  You may apply by April 15 at http://www.uthsc.edu/pharmacology /surf.php.

Name: Edward Chaum, MD, PhD
Department: Hamilton Eye Institute
Phone: 901-448-3638
Email: echaum@uthsc.edu
URL: http://www.eye.uthsc.edu/
dept/faculty/echaum.html

Project Title: Nanomaterial Applications in Ophthalmic Surgery
Project Summary: Development and testing of novel materials for applications in ophthalmic surgery. Methods include light and confocal microscopy, materials testing, and cellular and molecular biology.

Name:  Julio F. Cordero-Morales, PhD
Department:  Physiology
Phone:  901-448-8206
Email:  jcordero@uthsc.edu
URL:  http://corderovasquezlab.weebly.com/
(This lab may provide a summer stipend.)

Project Title: Studying TRP and Piezo channels for strategies to diminish neuropathic pain.

Pain is essential for survival and well-being. However, under certain conditions (diabetes, cancer, chemotherapy, heredity, infections, toxins) pain can become debilitating and decrease the quality-of-life of affected individuals. Neuropathic pain involves severe symptoms including stabbing pain, burning, tingling, loss of mechanical and thermal sensation, pressure and cold hypersensitivity, and balance problems. Transduction of painful stimuli involves excitatory ion channels, such as the transient receptor potentials (TRP) and Piezo channels at specialized sensory neurons that innervate our skin and organs. These channels respond to a variety of physical (e.g., heat and pressure) and chemical (e.g., fatty acids and cellular factors) stimuli to elicit or intensify pain.

Our goal is to elucidate the role of TRP and Piezo channels by delineating structural domains involved in channel activation, and identifying molecules that modulate its activity. We also seek to determine the contribution of bioactive lipids (released during inflammation) to TRP and Piezo activities in the context of the model worm Caenorhabditis elegans, since it has proven to be an excellent system to study pain.

Students will be directly involved with:

1- Functional determination of TRP channels using electrophysiology. Techniques in this project will include: molecular biology, cell culture, membrane protein purification, and patch-clamp technique.

2- Characterization of the interaction between Piezo and bioactive lipids in C. elegans. Techniques in this project will include: molecular biology, genetics, behavioral assays, RNAi, and in vivo Ca+2 imaging.

 

Name:  Valeria Vaxquez, PhD
Department:  Physiology
Phone:  901-448-7223
Email:  vvasquez@uthsc.edu
URL:  http://corderovasquezlab.weebly.com/
(This lab may provide a summer stipend.)

Project Title: Studying TRP and Piezo channels for strategies to diminish neuropathic pain.

Pain is essential for survival and well-being. However, under certain conditions (diabetes, cancer, chemotherapy, heredity, infections, toxins) pain can become debilitating and decrease the quality-of-life of affected individuals. Neuropathic pain involves severe symptoms including stabbing pain, burning, tingling, loss of mechanical and thermal sensation, pressure and cold hypersensitivity, and balance problems. Transduction of painful stimuli involves excitatory ion channels, such as the transient receptor potentials (TRP) and Piezo channels at specialized sensory neurons that innervate our skin and organs. These channels respond to a variety of physical (e.g., heat and pressure) and chemical (e.g., fatty acids and cellular factors) stimuli to elicit or intensify pain.

Our goal is to elucidate the role of TRP and Piezo channels by delineating structural domains involved in channel activation, and identifying molecules that modulate its activity. We also seek to determine the contribution of bioactive lipids (released during inflammation) to TRP and Piezo activities in the context of the model worm Caenorhabditis elegans, since it has proven to be an excellent system to study pain.

Students will be directly involved with:

1- Functional determination of TRP channels using electrophysiology. Techniques in this project will include: molecular biology, cell culture, membrane protein purification, and patch-clamp technique.

2- Characterization of the interaction between Piezo and bioactive lipids in C. elegans. Techniques in this project will include: molecular biology, genetics, behavioral assays, RNAi, and in vivo Ca+2 imaging.

 

Name: Ioannis Dragatsis, PhD
Department: Physiology
Phone: 901-448-3615
Email: idragatsis@uthsc.edu
URL: http://physio1.uthsc.edu/~dragatsisi/index.php and http://physio1.uthsc.edu/~dragatsisi/index.php

(This lab may provide a summer stipend.)

Project Title: Analysis of a mouse model for Familial Dysautonomia
Project Summary: 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 30. 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 normal function of huntington
Project Summary: 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.

Name: Maria Gomes-Solecki, DVM
Department: Molecular Sciences
Phone: (901)448-2536
Email: mgomesso@uthsc.edu
URL: http://www.uthsc.edu/molecular_sciences/directories/faculty/m_gomes.php

(This lab may provide a summer stipend.)

 

Title of Project: Oral Vaccines for Microbial Pathogens and Allergens

Project Summary (in non-technical terms):Our most challenging project relates to the development of a vaccine against peanut allergy. Peanut allergy is the major cause of fatal or near-fatal anaphylactic reactions to foods and affects 0.6% of US population. There is no vaccine available for peanut allergy and traditional immunotherapy using native peanut protein causes a high incidence of adverse reactions. We plan to develop oral vaccines in Lactobacillus plantarum and Lactobacillus casei, expressing three peanut allergens Arah1, Arah2 and Arah3, which have altered primary aminoacid sequences of the reactive IgE-binding epitopes. The major goal of this project is to test the efficiency of these oral vaccines in a mouse model of peanut allergy.

Another project relates to the development of a human oral vaccine against a Category B select agent, Burkholderia pseudomallei using the same Lactobacillus based platform technology described above. B. pseudomallei is a saprophyte that can be isolated from soil and is the causative agent of melioidosis in humans.

Name: Weikuan Gu, PhD
Department: Orthopaedic Surgery
Phone: 901-448-2259/577-7269
Email: wgu@uthsc.edu
URL: http://www.genediscovery.org/index.htm

(This lab may provide summer stipend.)

Title of Project:  Genetic and Genomic basis of human disease using mouse models
Project Summary (in non-technical terms): We are studying the genetic and genomic basis of human diseases using mouse models.   Several mouse mutants in our laboratory show the phenotype of human diseases.  Phenotypes of those mutations include bone fracture, arthritis, and ataxia.  We are using molecular tools such as microarray, and real time PCR to study the genetic pathways of the disease development and potential treatment.

 

Name:  Marcia Honig
Department: Anatomy & Neurobiology
Phone: 448-5998
Email: mhonig@uthsc.edu
URL: http://www.uthsc.edu/neuroscience/faculty/M_Honig.php

(This lab may provide summer stipend.)

Title of Project: Sensory axon guidance
Project Summary: My laboratory investigates how axons choose the correct pathways to grow along during development. We use the chick embryo as a model system because its easy accessibility allows us to perform experimental manipulations at virtually any point during embryonic development. Our work focuses on sensory neurons innervating the hindlimb and has shown that sensory neurons whose axons project along different peripheral nerves are different from one another at very early stages, before they make specific pathfinding decisions. Further, sensory axons respond to specific cues on one another and in the environment as they extend into the limb and grow to their appropriate targets.

My research is focused on understanding how neurons establish appropriate connections during development. As part of our previous work focusing on somatosensory neurons and using chick embryos as a model system, we identified the chicken homolog of cerebellin (Cbln) 2. Cblns are a family of four secreted proteins that, despite their name, are widely expressed in the nervous system and have been shown to promote synapse formation. In accord with this, we found that Cbln2 is expressed by specific subsets of neurons in the sensory ganglia and by neurons located in regions of the spinal cord where those sensory neurons project. To study Cbln function, we have transitioned to using mice as our experimental system because of the wealth of available genetic resources. Characterization of the distribution of Cblns1, 2, and 4 in the mouse spinal cord has demonstrated that each Cbln is expressed by discrete populations of neurons in the dorsal horn. To investigate the role of Cblns in the formation of sensory neuron synapses in the dorsal horn, we plan to examine how synaptic connections formed by specific kinds of sensory afferents with their targets in the dorsal horn are altered in Cbln1-null and Cbln2-null mice, through a collaboration with Jim Morgan at St Jude′s who has generated a variety of such knockout mice.

We are also currently developing a novel mouse model of mild-to-moderate spinal cord injury. This work uses an air blast cannon system (i.e. a modified paintball gun) that was designed to induce a non-invasive percussive injury. Our goal is to produce diffuse axonal injury, such as would occur when the spinal cord is stretched or deformed but the vertebral column remains intact, and thereby mimic the damage that frequently accompanies motor vehicle accidents, falls, and sports injuries. The injury will be evaluated using both behavioral assays and immunofluorescent labeling to examine effects on specific neuronal tracts. Future studies will elucidate the cellular and molecular mechanisms underlying the injury and assess possible therapies.

Name: Monica M. Jablonski, PhD
Department: Opthalmology
Phone: 901-448-7572
Email: mjablonski@uthsc.edu

(This lab may provide a summer stipend.)

 

Project Title: Genetic modulation of glaucoma
Project Summary (in non-technical terms): This project involves processing optic nerve samples and embedding them in plastic. After sectioning, the nerves will be assessed for damage.

Name: Len Lothstein, PhD
Department: Pharmacology
Phone: 901-448-3334
Email: llothstein@uthsc.edu

(This lab may provide summer stipend.)

Project Title: Antitumor and Cardioprotective Mechanisms of Cytoplasmic PKC Targeting Agents
Project Summary: Successful chemotherapeutic treatment of cancer is often limited by the development of drug resistance within the tumor cells and adverse systemic drug effects, particularly cardiotoxicity, which can be life-threatening. This project analyzes the mechanisms of action of a novel class of targeted antitumor agents. The apparent ability of the drugs to circumvent cellular drug resistance and act in a cardioprotective manner confers upon this class of targeted agents the potential to successfully treat refractory tumors with reduced toxicity for the patient.

 

Name: Kafait U. Malik, DSc, PhD
Department: Pharmacology
Phone: 901-448-6075
Email: kmalik@uthsc.edu
URL: http://www.uthsc.edu/vascular/Malik.Working.Group.htm

Project Title: Contribution of eicosanoids to adrenergic nervous and rennin-angiotensin system in the development of hypertension, vascular growth and restenosis during vascular injury
Project Summary: The objective of our study is to investigate how eicosanoids contribute to vascular wall remodeling by promoting vascular smooth muscle cell (VSMC) migration, proliferation, extracellular matrix production and/or hypertrophy during vascular injury and hypertension and the underlying mechanisms of these actions. Arachidonic acid (AA) and its metabolites have been implicated in these pathophysiological processes, but the mechanisms are not well understood. Our studies have shown that: a) AA and its metabolites derived via lipoxygenase [LO; 5(S)-, 12(S)- and 15(S)-hydroxeicosatetraenoic acids, HETEs] and via cytochrome P450 (CYP450; 20-HETE) and also angiotensin II (Ang II) (which causes release of AA) activate various signaling molecules (RasGTPase, MAPKs, p72Syk, EGFR, PI3Kinase, AKT) in VSMC; b) AA and Ang II-induced activation of these signaling molecules is attenuated by the inhibitor of AA metabolism 5,8,11,14, eicosatetraeynoic acid (ETYA); c) AA and its metabolites (HETEs), like Ang II, promote neointima formation in balloon injured rat carotid artery and increase blood pressure and f) Ang II induced neointima formation in the injured carotid artery and increase in blood pressure is attenuated by inhibitors of these signaling molecules. We are investigating the molecular mechanisms by which various signaling molecules mediate the effect of Ang II and adrenergic nervous system in neointimal growth, vascular growth and hypertension.

Name: Kristen O’Connell  
Department: Physiology
Phone: 901-448-2648
Email: kocone3@uthsc.edu

(This lab may provide summer stipend.)

 

Title of Project: Localization-dependent modulation of neuronal excitability by voltage-gated K+ channels.
Project Summary (in non-technical terms): Voltage-gated potassium channels (Kv channels) are crucial for the establishment and maintenance of neuronal excitability.  Their activity is essential for repolarization following action potential generation as well as in setting the firing rate for neurons throughout the brain.  At present, more than 40 Kv channel subunits have been cloned and functionally characterized and we now know that many of these channels are functionally quite similar, but most differ considerably in how they are modulated and where in the cell they are located (for example, some channels are found only on the cell body, while others are found only in axons or dendrites).
My lab is interested in the relationship between Kv channel localization and how these channels specifically modulate neuronal function.  We hypothesize that where a channel is physically located is a critically important factor in controlling excitability, possibly by positioning the channel in close proximity to the signaling pathways that modulate its activity.  Elucidating the mechanisms by which these channels are targeted to the appropriate subcellular domain is crucial for understanding how Kv channels contribute to diseases such as epilepsy, depression, stroke and many other neurological disorders.
Examples of potential projects are: 
1.  Characterize the localization of various Kv channels mammalian brain slices using immunofluorescence and live-cell microscopy. 
2.  Examine activity-dependent changes in channel localization and post-translational modification in cells expressing genetically-tagged Kv channels.
3.  Investigate how mis-targeting of Kv channels alters cellular excitability using electrophysiology.
Techniques used in the lab include:  immunofluorescence and live-cell microscopy, electrophysiology, Western blotting as well as molecular cloning and site-directed mutagenesis.

Name: Rennolds Ostrom, PhD
Department: Pharmacology
Phone: 901-448-1181
Email: mailto:rostrom@uthsc.edu
URL: http://ostrom.uthsc.edu/

 

Project Title: Compartmentation of receptors and their signaling pathways in heart and lung.
Project Summary: We are seeking to understand how cells "pre-arrange" multiple signaling components in G protein-coupled receptor signal transduction cascades and are focused on caveolae and lipid rafts as centers for such organization. Our long-term focus is to understand how such compartmentation impacts cellular response in a physiological setting. Using molecular cloning, expression of cloned signaling proteins, and a variety of cell biological and biochemical approaches, we examine signaling mechanisms of G protein-coupled receptors. We are interested in the organization of signaling microdomains in the plasma membrane, especially in lipid raft/caveolin-rich regions, in which various receptors, G-proteins and effectors, particularly certain isoforms of adenylyl cyclase, localize. We seek to understand how such compartmentation impacts on cellular responses with the goal of developing novel gene therapy strategies to modulate cellular responses through changes in expression of limiting components in the signaling pathways. Adenylyl cyclase is one such limiting component. Currently, we study cardiac myocytes, cardiac fibroblasts, airway and GI smooth muscle cells and pulmonary fibroblasts.

Name: Marko Radic, PhD
Department: Molecular Science
Phone: 901-448-8219
Email: mradic@uthsc.edu
URL: http://www.uthsc.edu/molecular_sciences/directories/faculty/m_radic.php

(This lab may provide summer stipend.)

Project Title: Induction of anti-nuclear autoantibodies
Project Summary: The Radic lab investigates possible mechanisms that initiate autoimmune reactions in humans and mouse models of autoimmunity.  Our focus is on autoantibodies and how they interact with their autoantigen targets.  Our working hypothesis is that the process of cell death produces and presents self antigens to the immune system in such a way as to stimulate an immune response.

Name: Anton Reiner, PhD
Department: Anatomy & Neurobiology
Phone: 901-448-8298
Email: areiner@uthsc.edu
URL: http://www.uthsc.edu/neuroscience/faculty/A_Reiner.php

(This lab may provide summer stipend.)

Title of Project: Animal Tests of Huntington’s Disease Treatments
Project Summary (in non-technical terms):  Using genetically engineered mouse models of Huntington’s disease, we use behavioral and histological methods to assess the ability of various treatments to treat Huntington’s disease.

Name: Lawrence T. Reiter, Ph.D.
Department:  Neurology
Phone: 901-448-2635
Email: lreiter@uthsc.edu
URL: http://curlyo.uthsc.edu/

(This lab may provide summer stipend.)

Project Title:  Ube3a regulation of the fly nervous system.
Project Summary:  We have identified changes in synaptic boutons in the fly larval neuromuscular junction that appear to be dependent on both Ube3a and at least one protein regulated by Ube3a in flies called Pbl.  The goal of this project is to generate double mutants for Ube3a and Pbl as well as Ube3a and Rac1/Rac2 (genes downstream of Pbl) in order to determine which aspects of the bouton number, bouton tract length and morphology are related to regulation by fly Ube3a.  The student should have a basic understanding of genetics, but we will teach them fly genetic methods.  This project will also involve dissection and antibody staining of fly neuromuscular junctions as well as statistical analysis of changes in bouton size and number.

Name: Tiffany N. Seagroves, PhD
Department: Pathology
Phone: 901-448-2259
Email: tseagro1@uthsc.edu

(This lab may provide summer stipend.)

Project Title I: Identification of the von Hippel-Lindau (VHL) - Regulated Proteome Using Transgenic Drosophila
Project Summary: Individuals with von Hippel-Lindau (VHL) disease have an increased risk of developing nervous system hemangioblastomas, pheochromocytomas and renal clear cell carcinomas (RCCs). In addition, VHL is mutated in the majority of sporadic RCCs. The tight, oxygen-dependent control of the stability of the Hypoxia-Inducible Factor (HIF) alpha protein subunits by VHL protein (pVHL) has been the focus of intense study. And, the inappropriate stabilization of HIF has been shown to contribute to tumorigenesis. Yet, evidence is emerging that there are also oxygen-independent pathways regulated by pVHL that may mediate tumor initiation and progression. For example, pVHL maintains the physical integrity of the cell through regulation of intra- and extracellular structural components. In addition, pVHL has been found to directly interact with other proteins besides the HIF subunits that may play a role in tumorigenesis. Although pVHL likely regulates the function of multiple genes at the protein level, there have been limited studies to determine the entire subset of proteins dependent upon pVHL expression. Furthermore, the majority of our knowledge of pVHL function has been derived from cultured cell lines. Finally, no protein profiling has been attempted within a whole model organism system. To address these concerns, we have created transgenic fruit fly stocks that express high levels of pVHL or dVHL (the fly protein) in response to heat treatment. We will search for and identify the subset of differentially expressed proteins between control and pVHL or dVHL transgenic flies. Only those proteins that are regulated by both pVHL and dVHL, and are, therefore, more likely to have a conserved function in humans, will be chosen for further analysis. Those candidates with a known connection to tumorigenesis will be prioritized. First, we will utilize RNA interference assays in Drosophila embryos to determine how candidate gene knockdown affects tracheal development and branching, which are known to be regulated by dVHL. Next, we will use VHL wild type (HEK 293T) or null (786-O) human cell lines to determine the functional significance of modulating expression levels of the human ortholog of the candidate to cell growth and motility. We believe that identifying the global network of VHL-regulated proteins will provide insight into the defects that give rise to tumors in VHL patients. Ultimately, our goal is to identify disease-associated candidates that are clinically relevant to VHL patients and are amenable to therapeutic intervention.

Project Title II: Understanding the Hypoxic Response in Mouse Models for Breast Cancer
Project Summary: In response to hypoxia, or the exposure to low levels of oxygen, tissues try to restore homeostasis by regulating cellular metabolism and by inducing growth of blood vessels. In addition, it is well-documented that adaptation to cellular stress induced by hypoxia is necessary for tumor progression since compared to normal tissues, nutrients and oxygen are rapidly depleted in tumors.  Furthermore, hypoxic regions of tumors are resistant to treatment with radiation and chemotherapy.  The expression, activity and protein stability of the master transcription factor hypoxia-inducible transcription factor (HIF)-1alpha is increased rapidly under hypoxic conditions, inducing several genes implicated in the regulation of glycolysis, angiogenesis and cell death.  In contrast, under normal conditions, the HIF-1alpha protein is rapidly degraded in the cell via targeted ubiquitination; this process is directed by its interaction with the von Hippel-Lindau (VHL) tumor suppressor protein (reviewed in Krek 2000). 
HIF-1alpha protein has been demonstrated to be up-regulated in poor grade, highly proliferating, breast tumors (Zhong et al. 2001), yet, the role of the hypoxic response during normal mammary gland function and its specific contribution to breast tumorigenesis has yet to be defined.  In order to define how hypoxia mediates these processes, I have deleted either the HIF-1alpha or VHL genes preferentially in the mammary epithelium of transgenic mice using a conditional deletion strategy.  These studies have revealed that HIF-1alpha is required for normal mammary epithelial cells to differentiate during pregnancy and to produce milk at lactation without impacting angiogenesis (Seagroves et al. 2003).  I am currently investigating the role of HIF-1alpha and VHL in breast tumor progression using transgenic mice that develop breast tumors (Liao et al. 2007).  My goal is to determine at which stage of tumorigenesis is the hypoxic response mediating tumor progression and to define the molecular mechanisms responsible for the adaptation of tumor cells to their hypoxic microenvironment.  We are also interested in the role that hypoxia/HIF/VHL may play in regulation of normal stem cells and cancer stem cells, which are predicted to be resistant to radiation and chemotherapy.   This research program is funded by the American Cancer Society.


Name:
Jena Steinle, PhD 
Department: Ophthalmology
Phone: 901-448-1910
Email: jjsteinle@uthsc.edu

(This lab may provide summer stipend.)

Project Title: Role of sympathetic nerves in diabetic retinopathy
Project Summary: We look at the mechanisms by which sympathetic nerves (fight or flight system) may result in the many retinal problems associated from diabetes. Investigations occur at the whole animal, cell culture, and molecular biology levels. Current work is focused on insulin signaling, inflammation, and apoptosis.


Name: Michael Whitt, PhD
Department: Molecular Sciences
Phone: (901)448-4634
Email: mwhitt@uthsc.edu
URL: http://www.uthsc.edu/molecular_sciences/directories/faculty/m_whitt.php

 

Title of Project:  “Development of oncolytic vectors for the treatment of glioblastoma”
Project Summary (in non-technical terms):  Glioblastoma multifome (GBM), a highly invasive and aggressive form of brain cancer.  Conventional therapies, such as surgery, radiation and chemotherapy are able to reduce the tumor burden and extend the survival of patients with GBM by a few months; however, these treatments rarely result in cure due to the invariable recurrence of tumor near the primary foci; therefore, novel therapies for the treatment of GBM are urgently needed.  As an alternative to standard of care therapies, we are developing novel viral vectors that are designed to be oncolytic (e.g. onco = tumor, lytic = killing) for the treatment of brain tumors. Specifically, we are using molecular biology techniques to create recombinant vesicular stomatitis viruses that have multiple mutations in the matrix gene which make them non-cytopathic for normal cells, but that retain efficient cytolytic properties against tumor cells.  The project will involve use of PCR-based mutagenesis to generate novel matrix mutations followed by transfection of cells with plasmids encoding the mutant proteins in culture to evaluate their cytopathic potential.  Mutations that have desirable oncolytic properties will be used to create novel recombinant viruses which will then be tested in a rat model of GBM.

 

Name: Xin Zhang, MD, PhD
Department: Medicine
Phone: 901-448-3448
Email: xzhang@uthsc.edu
URL: http://www.uthsc.edu/vascular/X.Zhang.faculty.htm

(This lab may provide summer stipend.)

Project Title: How tetraspanin suppresses tumor metastasis
Project Summary: KAI1/CD82 is a metastasis suppressor of solid tumors. The mechanism of KAI1/CD82-mediated metastasis suppression still remains largely elusive. Recent studies indicate that KAI1/CD82 induces the reorganization of membrane microdomains such as lipid rafts and tetraspanin-enriched microdomain (TEM), attenuates growth factor and integrin signaling, and inhibits cell protrusion and retraction. Notably, we also found that KAI1/CD82 suppresses cancer metastasis by inhibiting cancer cell invasiveness. Thus, how KAI1/CD82 inhibits cancer cell movement becomes the outstanding question to understand how KAI1/CD82 suppresses cancer metastasis. We hypothesize that KAI1/CD82 inhibits cancer cell migration and invasion through re-organizing membrane microdomains and consequently reducing protrusive and retraction processes and the outside-in motogenic signaling. To elucidate how KAI1 suppresses cancer invasion and metastasis, we will first carry out the structural and functional characterization of KAI1/CD82-containing TEM by i) identifying the structural element(s) in CD82 molecule that physically links TEM to lipid rafts, ii) systematically characterizing the protein and lipid components of CD82-positive TEM, and iii) analyze the trafficking and subcellular localization of CD82-containing TEM. Secondly, we will determine the mechanism by which KAI1/CD82-containing TEM regulates the cellular motile activities by addressing how CD82-containing TEM renders membrane curvature and trafficking. We will also assess the roles of CD82-induced alterations in membrane curvature and trafficking in i) membrane motile activities, ii) motogenic signaling, and iii) CD82-mediated suppression of cancer invasion. Finally, we will determine the mechanism by which KAI1/CD82 inhibits cancer invasion in vivo by addressing i) through which cellular motile activity CD82 suppresses cancer invasion in vivo, ii) the contributions of the proteins physically or functionally associated with CD82 to CD82-mediated suppression of cancer invasion; and iii) whether the CD82 features analyzed above are crucial for its suppression of cancer invasion in vivo. Together, the proposed study will enable us to i) understand how KAI1/CD82 regulates cell migration, cancer invasion, and cancer metastasis as an organizer for membrane microdomains and ii) unveil a novel mechanisms by which cell motility and cancer metastasis are regulated, i.e., membrane curvature and trafficking regulates invasion and metastasis. From the in-depth in vitro and in vivo mechanistic study of KAI1/CD82, we will develop an integrated understanding of cancer invasion and metastasis, which will ultimately lead to the development of KAI1/CD82 into a diagnostic marker and therapeutic target for cancer invasion and metastasis.

Name: Fu-Ming Zhou, PhD
Department: Pharmacology
Phone: 901-448-1779
Email: fzhou3@uthsc.edu
URL: http://www.uthsc.edu/neuroscience/faculty/F_Zhou.php

(This lab may provide summer stipend.)

Project Title: Brain Dopamine and Serotonin
Project Summary: Study the cellular and molecular mechanisms of the brain dopamine and serotonin systems in drug addiction, depression, schizophrenia, and Parkinson’s disease.