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Potential Faculty Mentors, Project Titles and Descriptions for Research Semester 2014 Faculty Mentor Ahn, Changwoo Associate Professor Department of Environmental Science and Policy Ascoli, Giorgio Professor, Molecular Neuroscience, Krasnow Institute for Advanced Study Baranova, Ancha Associate Professor, School of Systems Biology; Director, Study of Chronic Metabolic Diseases and Birerdinc, Aybike Research Assistant Professor, School of Systems Biology; Assistant Director, Study of Chronic Metabolic Diseases Blackwell, Kim L. (Avrama) Professor, Molecular Neuroscience, Krasnow Institute for Advanced Study Cox, Daniel Associate Professor and Graduate Program Director, School of Systems Biology and Krasnow Institute for Advanced Study Title of Project and project number 1. Effects of Plant Diversity on Soil Quality Development in Mesocosm Wetlands 2. Soil Bacterial Community Patterns 3. Hippocampome Project Contact Information Changwoo Ahn [email protected] Giorgio Ascoli [email protected] 4. NeuroMorpho.Org 5. Molecular Pathways Involved in the Pathogenesis of NonAlcoholic Fatty Liver Disease and Other Obesity Related Pathologies 6. Candidate genes in esophageal cancer: Novel Human Tumor Suppressor Gene Candidates Identified by Exome Sequencing Baranova, Ancha [email protected] Birerdinc, Aybike [email protected] 7. The Development of In Vitro System for Migraine Studies NB: Research site - Inova Hospital on Gallows Road 8A. and 8B. Signaling pathways involved in striatal synaptic plasticity Avrama Blackwell [email protected] 9. Transcriptional and Cytoskeletal Control Mechanisms of Dendrite Development Daniel N Cox [email protected] 10. Epigenetic Regulation Via MicroRNAs of Class Specific Dendrite Morphogenesis 1 de Mutsert, Kim Assistant Professor, Department of Environmental Science & Policy Dumas, Theodore Assistant Professor of Molecular Neuroscience, Krasnow Institute for Advanced Study 11. Genetic Analysis of Pain Sensation in Response to Noxious Cold Stimuli 12. Fish diets and food webs in tidal freshwater ecosystems 13. The larval fish community composition of tidal freshwater ecosystems 14. Pharmacological Ignition of Hippocampal Function In Juvenile Rats Kim de Mutsert [email protected] Theodore C Dumas [email protected] 15. Synaptic and Cognitive Development in NMDA Receptor Chimeric Mice 16. Neuronal Silencing the Mouse Hippocampus Using the Fly Allatostatin Receptor 17. Tardigrades and the Survival of Learned Information in a Cryogenic Regime (with Dr. Harold Morowitz) Frankenfeld, Cara Assistant Professor, Global & Community Health, College of Health & Human Services Gallo, Sina Assistant Professor, Department of Nutrition and Food Studies College of Health and Human Services Gillevet, Patrick Professor, Department of Environmental Science and Policy Director, MicroBiome Analysis Center 18. Nutrition and Environmental Risk Factors for Human Health Conditions Cara Frankenfeld [email protected] 19. Predictors of Adiposity in Preschool-Aged Children Sina Gallo [email protected] 20. Metabiome of Human Disease Patrick Gillevet [email protected] 21. Microbial Ecology of Environmental Disease 2 Grant, Geraldine M. Associate Professor, School of Systems Biology 22. Studies of Idiopathic Pulmonary Fibrosis A. Over expression of KLF4 in Idiopathic Pulmonary Fibrosis (IPF) Geraldine M Grant [email protected] B. Localization of KLF4 in Idiopathic Pulmonary Fibrosis (IPF) by immunohistochemistry. C. Effect of cytokine exposure on the activation status of a novel human lung fibroblast population. D. Investigations for novel surface and secreted markers for human fibroblasts and myofibroblasts in IPF. 23. Tissue Engineering Hakami, Ramin Assistant Professor, School of Systems Biology Hamdan, Leila J. Assistant Professor, Department of Environmental Science and Policy Jafri, Saleet Professor, Bioinformatics & Computational Biology, School of Systems Biology and Krasnow Institute for Advanced Study Jones, R.C. Professor, Department of Environmental Science and Policy 24. Exosome-mediated intercellular communication during bacterial infections. Ramin Hakami [email protected] 25. Host signaling during infection with biodefense bacterial agents. 26. Microbial ecology of the marine deep biosphere [email protected] 27. Systems Biology Approaches to Understanding Cardiac Arrhythmias Saleet Jafri [email protected] 28. Water Quality and Aquatic Ecology in The Tidal Potomac River and its Local Tributaries R Christian Jones [email protected] 3 Kabbani, Nadine Assistant Professor, Molecular Neuroscience, Krasnow Institute for Advanced Study Luther, David Assistant Professor, Biology Department Kehn-Hall, Kylene Assistant Professor, National Center for Biodefense & Infectious Diseases, School of Systems Biology 29. Axon Growth and Regeneration in the Brain Nadine Kabbani [email protected] 30. The Evolution of Acoustic Competition in Songbirds David Luther [email protected] 31. Novel Therapeutics for Viral Infections Kylene Kehn-Hall [email protected] Paige, Mikell Assistant Professor, Department of Chemistry & Biochemistry 33. Design and Synthesis of Inhibitors of Protein-Protein Interactions for the Treatment of Cancers Peters, Esther Associate Professor, Department of Environmental Science and Policy Pollack, Anna Assistant Professor, Global & Community Health College of Health & Human Services Popov, Serguei Professor, Center for Biodefense & Infectious Disease, School of Systems Biology 32. Secretome of Viral Infections Mikell Paige [email protected] 34. Synthesis and Characterization of a Breast Homing Peptide Conjugate for the Treatment of Breast Cancer 35. Investigating the Pathobiology of Lung Cancer 36. Using Histology to Understand Interactions between Organisms and the Environment Esther Peters [email protected] 37. Environmental Chemical Exposure and Women’s Health Anna Pollack [email protected] 38. Novel Aspect of Anthrax Toxicity: Role of Reactive Oxygen and Nitrogen Species Generated by Bacterial Cells. Serguei Popov [email protected] 39. Nanoparticles for Interrogation of the Infectious Disease Mechanisms 4 Van der Ham, Joris Adjunct Assistant Professor, Department of Environmental Science and Policy 40. Biodiversity of Virginia Spring Seeps 41. Succession of Invertebrate Communities in Potomac Tributaries Joris Van der Ham [email protected] 42. Insects of the George Mason University campus van Hoek, Monique Associate Professor, School of Systems Biology 43. Antimicrobial Peptides Monique Van Hoek [email protected] Willett, James D. Professor and Director, School of Systems Biology Wu, Yuntao Professor, School of Systems Biology 45. Exploring Metabolic Changes in Very Old Nematodes Willett Jim [email protected] 46. Role of Pyk2 activation in HIV infection Yuntao Wu [email protected] 44. Novel Antibiotics 47. Role of Jak/Stat pathway in HIV infection 5 Description of Potential Projects for Research Semester, Fall 2014 1. Effects of Plant Diversity on Soil Quality Development in Mesocosm Wetlands This study investigates the nutrient levels in tissues in wetland plants and calculates the ratios of carbon, nitrogen, and phosphorus, aiming to test if the ratios can be used as an indicator for predicting productivity of a wetland. The project also involves studying the relationship between plant diversity and productivity in created wetlands. 2. Soil Bacterial Community Patterns This study investigates soil bacterial community patterns as affected by initial planting richness in three year old mesocosm wetlands. The student will conduct DNA extraction from mesocosm soil samples and fingerprint them using T-RFLP, and analyze them by different make-up of wetland vegetation. There is a potential for the student to be trained in molecular analysis of samples at the USGS, Reston, VA. 3. The Hippocampome Project In the same vein as a genome, the Hippocampome is envisioned as the ultimate knowledge base describing the structure, activity, and function of the hippocampus, the brain region responsible for processing conscious autobiographic memories and plans. The foundation of this project is a catalogue of the many classes of neurons found in the hippocampus and the wiring diagram that interconnects all of them. The descriptions of these classes are distilled from data published in peer-reviewed journals. Compiling and collating all of this knowledge into a single computerized resource will uncover new correlations and interrelations that will help discover the cellular mechanisms of hippocampal function and dysfunction. The student will learn to identify dendritic and axonal morphologies, microscopy techniques for their visualization, how they relate to the surrounding nervous tissue, and their effect on neuronal activity and network function. See also http://hippocampome.org and http://krasnow.gmu.edu/cn3 4. NeuroMorpho.Org NeuroMorpho.Org is a central, one-of-a-kind online neuroscience resource that provides free worldwide access to 3D digital reconstructions of neurons. Neurons are traced from microscopy imaging in many types of research laboratories, from the study of pharmacology to that of development. These same data can be reanalyzed for additional discoveries, including computational models of brain function. Data are 6 deposited in NeuroMorpho.Org from various species ranging from flies, to rats, to humans, to elephants. Millions of neurons have been downloaded in more than 100 countries. NeuroMorpho.Org is a leading project in the emerging trend of data sharing in the neuroscience community that aims to maximize the research potential of collected data. The student will learn to identify dendritic and axonal morphologies, microscopy techniques for their visualization, how they relate to the surrounding nervous tissue, and their effect on neuronal activity and network function. See also http://NeuroMorpho.Org 5. Molecular Pathways Involved in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Other Obesity Related Pathologies Obesity is the abnormal or excessive increase in adiposity. Lately, obesity has got attention as the state of low grade chronic inflammation characterized by both macrophage infiltration of AT and increased production of pro-inflammatory cytokines that play a role in insulin resistance (IR). Non-alcoholic fatty liver disease (NAFLD) is a common disease that comprises a morphological spectrum of liver pathologies ranging from simple triglyceride accumulation in hepatocytes (fatty liver or hepatic steatosis) to inflammatory conditions (non-alcoholic steatohepatitis; NASH), eventually leading to fibrosis and cirrhosis. The major goals of the proposed studies are designed to provide novel insight into the molecular mechanisms by which adipose tissue of obese individuals promotes the development of secondary complication of obesity. Techniques: ELISA assays, Bio-Plex assays, qRT-PCR, Cell culture 6. Candidate genes in esophageal cancer: Novel Human Tumor Suppressor Gene Candidates Identified by Exome Sequencing Eleven NGS exome sequences have been performed on patients with genetic predisposition to esophageal cancer, from the same region. I have long lists of variations, and I will need a student to analyze these variations for their functional meaning and narrow down candidate gene lists for further studies. Preliminary work will be performed in the Spring 2014 semester. The Fall student will pick up where the other student leaves off and proceed with experimental studies of select candidates in a cell-based system. 7. The Development of In Vitro System for Migraine Studies Migraine is a painful neurological disorder that affects 16% of the general population. Most commonly known triggers include sensory stimuli (light, smell), stress, changes in sleeping pattern or environment and certain foods. Serum levels of CGRP (Calcitonin Gene Related Peptide) are elevated in patients during migraine and cluster headaches. The ability of injected CGRP to induce migraine like headaches and of a CGRP receptor antagonist to provide relief in migraine clinical trials has established the 7 involvement of CGRP in migraine. The aim of this/the project is to determine the expression of Cgrp in CA77 cells after exposure to potential migraine provoking food compounds. The cell line used for research is thyroid C-cell line, CA77 that is derived from calcitonin secreting endocrine cells of neural crest origin. CA77 cells possess neuronal properties. RT-qPCR will be used to monitor the CGRP expression to identify the chemicals that affect the development of migraine. This research project would generate and characterize a valuable model that will eventually help to understand the effect of exposure to various triggering food components on the pathogenesis of migraine. This research study is focused on the screening of migraine-provoking food compounds. We expect to quantify expression levels of Cgrp in the CA77 cells before and after exposure to a number of potential migraine provoking foods and measure the Cgrp expression by using qPCR technique. 8. Signaling Pathways Involved in Striatal Synaptic Plasticity The striatum is a brain structure that governs habit and skill learning. In addition, Parkinson’s Disease and Huntington’s Disease are neurodegenerative diseases that involve the striatum. In this structure, the main neurons are the medium spiny projection neurons (MSPNs). They receive both excitatory inputs from the cerebral cortex, and dopamine inputs. Learning occurs when the cortical inputs and dopamine inputs are activated with appropriate temporal interval. We are studying the mechanisms that produce the plasticity underlying learning in striatal neurons. 8A) One project involves behavioral and electrophysiological experiments. The student will train rats to learn that turning in one direction is rewarded. Early in training this task requires the hippocampus, but later in training, when it has become a habit, the task requires the striatum. In addition, the student will learn to do electrophysiology, and evaluate the conditions that produce plasticity. Specifically, the student will investigate the dependence of plasticity on dopamine receptors and also acetylcholine receptors. 8B) A second project involves computer modeling. The student will develop biochemical kinetic models of signaling pathways underlying striatal synaptic plasticity. Knowledge of calculus and computer programming is advantageous but not required. The student will learn how experimental design applies to computer simulations. 9. Transcriptional and Cytoskeletal Control Mechanisms of Dendrite Development The major goals of the proposed studies are designed to provide novel insight into the molecular mechanisms by which transcriptional and cytoskeletal regulation mediate class-specific dendrite homeostasis. We have identified a broad set of transcription factors that exhibit differential gene expression among distinct subclasses of neurons via class-specific microarray analyses and have been demonstrated to function 8 in the specification of differential dendrite morphology. Specific functional areas of interest that are under transcriptional control include: autophagy, ribosome biogenesis, and cytoskeletal regulation. This project will afford students the operate to explore one or more of these questions using novel genetic tools and state-of-the-art cellular imaging techniques. This project likewise offers opportunities for students interested in genomic analyses and computational modeling/modeling. Techniques: advanced genetics for temporal and spatial control of gene expression, phenotypic analyses of living neurons in real time, molecular biology, three-dimensional confocal laser scanning microscopy, and quantitative digital reconstructions of neuronal morphology. 10. Epigenetic Regulation via MicroRNAs of Class Specific Dendrite Morphogenesis The major goals of the proposed studies seek to investigate the regulatory and epigenetic effect of microRNAs (miRNA) on differential dendrite morphogenesis within distinct neuronal subtypes. miRNAs play a critical role in post-transcriptional regulation of gene expression within the genome and we have demonstrated via miRNA microarrays that there is differential expression of miRNAs in different neuron subclasses. Moreover, through a genome-wide screen we have identified and initially characterized >75 miRNAs that regulate this process. The proposed project will further explore the effects of of these miRNAs and their regulatory mRNA targets in Drosophila sensory neurons and examine in living organisms how these miRNAs mechanistically control unique aspects of dendrite development. Techniques: advanced genetics for temporal and spatial control of gene expression, phenotypic analyses of living neurons in real time, molecular biology, three-dimensional confocal laser scanning microscopy, and quantitative digital reconstructions of neuronal morphology. 11. Genetic Analysis of Pain Sensation in Response to Noxious Cold Stimuli Elucidating the cellular and molecular mechanisms that regulate somatosensory signaling is critical in identifying and implementing novel strategies for the treatment of pain. Nociception, the process of encoding and transmitting noxious stimuli within the nervous system is essential for organism survival, however can also manifest as undesirable pain sensation. The proposed studies will explore the cellular and molecular bases of noxious cold nociception under acute conditions using the fruitfly Drosophila melanogaster as a model system. While select members of the Transient Receptor Potential family of ion channels have been implicated in noxious thermosensation, our understanding of the mechanisms and signaling pathways by which these channels function in cold transduction, as well as the identity of cold sensing nociceptors, is far from complete. Using our newly developed behavioral response assay for noxious cold transduction in Drosophila larvae, we will employ in vivo genetics and transgenic tools to identify and molecularly characterize cold sensing nociceptors. 9 Techniques: advanced genetics for temporal and spatial control of gene expression, phenotypic analyses of living neurons in real time, threedimensional confocal laser scanning microscopy, behavioral assays, high-resolution Ca2+ imaging, and quantitative digital reconstructions of neuronal morphology. 12. Fish Diets and Food Webs in Tidal Freshwater Ecosystems Reconstruct the complex food web of Potomac River tributaries through stomach content analysis. The study will include fieldwork to collect fish, and lab work during which the diet items will be identified. In combination with stable isotope analysis, this work will help determine if the association of fish with specific habitats or locations will be reflected in their diet, and what consequences habitat alterations have for Potomac River food webs. 13. The Larval Fish Community Composition of Tidal Freshwater Ecosystems This project will aid in the understanding of spawning patterns of fish in freshwater tidal ecosystems. Lab work will include analyzing ichthyoplankton samples collected in Gunston Cove and Hunting Creek to identify the species and determine abundance. Research questions can include: what is the seasonal spawning pattern of fish in these environments? What is the community structure and abundance of larval fish in Gunston Cove and/or Hunting Creek? How does this relate to the abundance and community composition of adult fishes in these environments? How important is Gunston Cove as larval fish habitat as compared to Hunting Creek? What environmental factors could be responsible for potential differences? 14. Pharmacological Ignition of Hippocampal Function in Juvenile Rats Episodic memories are memories of one's personal experience. The hippocampus is the primary brain structure involved in forming episodic memories. How hippocampal neurons operate to encode episodic memories is presently unclear, but appears to involve activity-dependent functional alterations at synapses, the communication points between neurons. Interestingly, episodic memories are not formed until late in the postnatal period across mammalian species, suggesting delayed development of the hippocampus. As such, the developmental emergence of episodic memory presents a valuable model for understanding the neuronal properties that are critical for memory formation. We have found that excitatory synapses in the rat hippocampus are weak in their ability to activate postsynaptic neurons until the end of the third postntatal week. This is the same age at which hippocampal-dependent learning and memory abilities are first observed in this species, suggesting that insufficient synaptic excitation limits memory formation or retrieval. Drugs that cause excitatory synaptic responses to last longer also increase postsynaptic activation in juvenile rats. We have delivered the same drugs to behaving animals and examined their ability to learn hippocampaldependent maze tasks. We have preliminary evidence that suggests that prolonging excitatory synaptic responses improves memory in 10 juveniles. Current experiments test the impact of prolonged synaptic excitation on synaptic plasticity and network activity patterns during maze exploration. 15. Synaptic and Cognitive Development in NMDA Receptor Chimeric Mice Neural network development and information processing in the brain both require synaptic plasticity. As circuits in the mammalian forebrain mature, synaptic plasticity is adjusted to better suit information processing. Disruption of this process has been implicated in various neurodevelopmental disorders, including autism spectrum disorders. In the rodent hippocampus, this transition happens late in postnatal development, culminating in the emergence of hippocampal-dependent learning and memory abilities at the end of the third postnatal week. This research aims to explore the molecular determinants of the developmental alterations in synaptic plasticity and emergence of cognitive abilities. Forebrain glutamatergic N-methyl-D-aspartate receptors (NMDARs) exist primarily as quatramers with two NR1 and two NR2 subunits. Auxiliary NR2 subunits regulate numerous facets of receptor function. Conductance regulating domains exist in the extracellular amino and transmembrane regions while synaptic targeting and intracellular signaling domains exist in the intracellular carboxy terminus. At hippocampal Schaffer collateral (SC-CA1) synapses, NMDARs contain predominantly NR2B subunits during early postnatal development and NR2A subunits after the end of the third postnatal week. As such, the developmental NR2 subunit switch produces numerous changes in NMDAR function. Interestingly, the shift in NMDAR composition parallels developmental changes in the ability to induce activity-dependent synaptic plasticity and completion of the shift marks the onset of adult-like spatial navigation. We have generated transgenic mice that express NMDARs with chimeric NR2 subunits at SC-CA1 synapses, which allows for separation of the NR2-dependent conductance and intracellular signaling properties. We are currently conducting research the molecular, physiological, and behavioral level to better understand which NMDAR properties are most closely related to the age-related changes in synaptic plasticity and in learning and memory abilities 16. Neuronal Silencing the Mouse Hippocampus Using the Fly Allatostatin Receptor Your brain is made up of billions of neurons each having thousands of communication contact sites. As such, the complexity of brain circuitry is amazing complex. This complexity makes it difficult to draw precise relationships between neuron function and behavior. Traditionally, this has been attempted with lesion studies to eliminate small regions of the brain prior to maze training. Unfortunately, virtually all lesions procedures lack the precision to eliminate specific subpopulations of neurons interspersed with other neuron types and are permanent. Recent advances in genetic tools have produced the ability to functionally silence highly specific subsets of neurons in a reversible manner. This allows for noninvasive circuit analysis in awake behaving mice. One of these methods involves expression of the fly allatostatin receptor (AlstR). When activated, this receptor maintains neurons in a hyperpolarized state, in essence, functionally removing them from ongoing activity. We are 11 examining the impact of AlstR expression and activation in specific sets of hippocampal neurons to better relate their function to specific aspects of hippocampal-dependent learning and memory abilities. 17. Tardigrades and the Survival of Learned Information in a Cryogenic Regime Memory refers to the storage of information across time. Historically, information storage in a biological system has been seen as requiring either a persistent structural or functional change at the cellular level. Whether a memory relies on a structural or functional alteration in neurons is a difficult question to address in most model systems as one cannot fully separate structure from function at the cellular and molecular levels. In this regard, tardigrades of the genus hypsibius (water bears) become an important neuroscience subject. Tardigrades are microscopic multicellular organisms with a nervous system. They are special organisms in that they can survive absolute zero and a complete vacuum by taking on a "tun" state in which metabolism ceases. Tardigrades can be used to separate the structural and functional contributions to memory because all neuronal dynamics can be stopped and restarted during the storage phase. We train tardigrades in chemoaversive or chemoattractive tasks and then dessicate them and store them at ultracold temperatures. Upon revival, we test them to see if they remember what they learned prior to being freeze dried. 18. Nutrition and Environmental Risk Factors for Human Health Conditions Epidemiology is the study of the distribution and determinants of disease frequency in human populations and the application of this study to control health problems. Student/s will analyze existing human data to evaluate nutritional and environmental risk factors, including phytoestrogens, environmental toxins, or geographic location. Work may involve analyzing nutrient intake from dietary records, evaluating dietary and environmental biomarkers from existing data, or comparing different methodologies. Specific diseases and health conditions that student/s may evaluate include obesity, metabolic syndrome, or other chronic health conditions. Student/s will integrate biology knowledge with the application of epidemiological and biostatistical concepts. 19. Predictors of Adiposity in Preschool-Aged Children Childhood obesity has tripled among US youth in the last three decades. There are immediate and long term consequences for obese children including increased risk for developing metabolic and cardiovascular diseases. The critical periods of pregnancy, infancy and early childhood may be a crucial time for interventions. In particular, behaviors formed during the preschool years have the potential to prevent obesity in the short term and even into adulthood. The student will work on data that has been collected over the summer 2014 to identify individual and social 12 predictors of adiposity in 2-5 year old children attending daycares in Northern Virginia. Particularly, assess the prevalence of overweight/obesity and describe body composition in this age group. Utilize diet analysis software to assess nutrient intake and compare to national guidelines. Use advanced statistical modeling techniques to examine the relationship between lifestyle, contextual factors (e.g., parental stress, socio-culturaleconomic factors) and obesity among pre-school aged children. 20. Metabiome of Human Disease We have been applying a systems biology approach to characterize the Metabiome of these host and microbial communities (microbiome) to determine which features are associated with the disease state. We define the Metabiome as all the interactions between the host and the microbiome. The initial thrust is based on Knowledge Discovery to define the correlations between features and disease classes but the ultimate goal is to develop new hypothesis that can then be tested using traditional hypothesis driven experimental procedures. We are looking at a number of human diseases that are associated with dysbiosis of the bacteria community in the human gut. These include Alcoholic Liver disease, Inflammatory Bowel Disease, Autism, and Colon cancer. Students will have the opportunity to work in the wet lab using NexGen sequencing, metabolomics, and transcriptomics technology and state-of-the-art bionformatics pipelines. 21. Microbial Ecology of Environmental Disease We have been applying a systems biology approach to characterize microbial communities in the natural environment. These studies involve characterization of complex microbial commnities and natural environments and looking at metabolic and expression functionality of these system. We are looking at a number of diseases or conditions that are driven by environmental factors such as Coral Diseases and Lobster Shell disease. We are also look at bioremediation processes in oil spills and the biogeochemistry of natural cold seeps. Students will have the opportunity to work in the wet lab using NexGen sequencing, metabolomics, and transcriptomics technology and state-of-the-art bionformatics pipelines. 22. Studies of idiopathic pulmonary fibrosis Idiopathic Pulmonary Fibrosis is a fatal interstitial lung disease that kills over 40,000 individuals each year – more than die from breast cancer. Currently there are not therapies and no cure for this disease and patient survival time post diagnosis is less than 5 years. There are a number of projects currently available in my lab to investigate the potential role of particular proteins in IPF. 13 A. B. C. D. Localization of Krupple like transcription factor 4(KLF4) in Idiopathic Pulmonary Fibrosis (IPF) The exact location of KLF4 within the IPF lung is not known. This project will use immunohistochemistry on IPF and normal fixed tissue slices to locate KLF4 in this tissue in addition its association with another factor associated with IPF. Over expression of Krupple like transcription factor 4(KLF4) in Idiopathic Pulmonary Fibrosis (IPF) While we know that KLF4 is over expressed in IPF fibroblast, we do not know what contribution this makes to IPF. This project will involve overexpressing KLF4 in Normal human lung fibroblasts and documenting the resulting in change in phenotype in these cells. Effect of cytokine exposure on the activation status of a novel human lung fibroblast population. Cytokine exposure plays a major role in the differentiation of human fibroblasts in the wound response – the pathway which is believed to be out of control in IPF. Transforming growth factor beta – TGFB1 is the most prevalent cytokine expressed in IPF and is capable of transforming normal fibroblasts into their activated wound repairing myofibroblast phenotype. We have isolated a novel population of Normal and IPF fibroblasts. The response of these cells to TGFbeta and any other IPF related cytokine is unknown. This project involves the exposure of these cells to TGFb1, IL1beta, PDGF and TNFalpha. Investigation for novel surface marker for human fibroblasts and myofibroblasts. Fibroblast biology and investigations are marred by the lack of a suitable marker for their isolation. At present fibroblasts are isolated by outgrowth from tissue pieces…a procedure that results in loss of phenotype and dedifferentiation of cells to a “fibroblast-like” phenotype. The only currently accepted marker for fibroblasts is expression of alpha smooth muscle actin (alpha-SMA) – an internal marker and of no use in isolation of fibroblasts in mixed cell culture. We have isolated a novel population of fibroblasts by differential binding from both IPF and normal tissue. In addition, we have carried out extensive genomic analysis. This project will involve analysis of large genomic data sets to derive a candidate list for common surface markers between both populations AND exclusive surface markers that may serve as a biomarkers and tools for isolation 23. Tissue Engineering Tissue engineering is a rapidly expanding area with great potential. In vitro engineering of chondroctyes, the cells responsible for cartilage is of paramount importance for autologous transplantation – therapy available for those with cartilage defects and injury. However these cells when grown in the lab – a step required for this treatment, dedifferentiate. The resulting cells are chondrocyte like, but do not behave exactly as normal chondrocytes would. One gene expression that is lost during growth in the lab is Krupple like factor 4 (KLF4). This protein has many roles, however its loss in culture suggest its importance for chondrocyte health. This project involves reintroducing KLF4 by transfection into normal articular chondrocytes and observing the changes that occur in these cells. 14 24. Exosome-mediated intercellular communication during bacterial infections Exosomes are small membrane bound extracellular vesicles that carry biological macromolecules from the site of production to target sites either in the microenvironment or at distant sites away from the origin. Recent studies have demonstrated that exosomes play a significant role in cell-cell signaling, cancer progression, host immune responses, infectious diseases, and even as carriers of prions, and The role of exosomes during the progression of infection is a subject that has garnered enormous interest in recent years. The focus of our research is to understand the fundamental mechanisms of how exosomes are involved during infection with pathogenic bacteria or viruses, including infection with the biodefense agents Yersinia pestis (Yp) and B. pseudomallei (Bp). We have examined various purification strategies for isolation of CD63+ exosomes released from a human monocytic cell line infected with Yp, and have performed a comparative analysis of exosomal miRNA profiles between infected and uninfected cells. Our results have shown that distinct exosomal populations are released from cells and have also demonstrated the enrichment of specific miRNAs within exosomes obtained from infected cells. Students on this project will perform functional studies of specific miRNAs that show strong enrichment in exosomes derived from infected cells. During the course of this project students will learn several main and important microbiology-related techniques, including culturing bacteria, measuring bacterial growth, setting up infection experiments, tissue culture techniques, protein analysis techniques such as Western blot analysis, cell staining, and microscopy techniques. In addition, students will learn the techniques for isolation and characterization of exosomes. 25. Host signaling during infection with biodefense bacterial agents. New drugs with greater potency against bacterial infections are urgently needed in order to combat bacterial infections more efficiently and to counter naturally occurring and man-made antibiotic resistant strains. One main focus of our research is discovery of new measures to combat the biodefense agents Y. pestis (Yp) and B. pseudomallei (Bp), two agents for which effective therapeutic measures are needed. Yp is a model organism for pathogenic gram-negative bacteria and is the etiological agent of the plague. Yp can cause high mortality rates, especially in pneumonic form. Plague is now categorized as a reemerging disease given the rise in the number of reported human cases during the past two decades and the reappearance of outbreaks in various countries after decades of quiescence. Yp is also of great concern given the documented history of its use in biowarfare and the potential for its use for bioterrorism considering its high lethality and relative ease of production. Similar to Yp, Bp is a gram-negative biodefense agent. Bp can cause disease in both humans and animals and can infect a wide range of animal species, including mammals, bird, and shellfish. In humans, Bp causes melioidosis, often characterized by fever, cough, and chest pain in patients that present with the 15 active form of the disease. Discovering host signaling pathways of importance that are engaged by dangerous pathogens such as Yp and Bp could lead to discovery of novel and potentially multiagent therapeutic measures that are immune to development of antibiotic resistance mechanisms. To address this critical need, students will perform functional studies of host signaling proteins that are involved during Y. pestis and B. pseudomallei infection, in order to understand the roles that these proteins play during infection. Only highly attenuated strains of Yp and Bp (approved for BSL-2) will be used. The important host proteins that have been identified and selected using a novel protein microarray platform called RPMA will be studied for their roles during infection. Students will learn several main and important microbiology-related techniques, including culturing bacteria, measuring bacterial growth, setting up infection experiments, tissue culture techniques, protein analysis techniques such as Western blot analysis and immunoprecipitation, cell staining, and microscopy techniques. 26. Microbial ecology the marine deep biosphere. The marine deep biosphere (MDB) is the area in the ocean that exceeds 200m water depth. The MDB includes vast tracts of water and subsurface sediments. Because of its tremendous volume it is estimated that 92% of Earth’s microorganisms are found in the MDB. This environment is difficult to access, and as a result is poorly understood. However, recent studies demonstrate that the MDB is highly diverse, and contains microorganisms uniquely suited to live in permanently dark, cold and deep locations. This project will use existing samples from the MDB to study microbial community composition, biodiversity, function and density. Molecular and microbiological approaches will be utilized to provide a comparison of microbial communities from various locations around the world to determine the features that shape microbial communities and their biogeography. 27. Systems Biology Approaches to Understanding Cardiac Arrhythmias In this project the student will use computer simulation to study how molecular level events lead to cardiac arrhythmias. This multi-scale approach allows a quantitative study that integrates experimental information as different levels to get a systems perspective on cardiac arrhythmias. The project will involve interacting closely with experimental scientists. A desire to do computer programming is required. 28. Water Quality and Aquatic Ecology in the Tidal Potomac River and its Local Tributaries Specific topics available include: water quality monitoring, E. coli monitoring, stream macroinvertebrates and periphyton, river plankton dynamics, and harmful algal blooms. 16 29. Axon Growth and Regeneration in the Brain Our laboratory studies the molecular mechanisms by which nicotinic acetylcholine receptors (nAChRs) signal and operate in the developing and adult brain. We are investigating how nAChRs direct neuronal development by examining the role of nAChRs in growing axons and growth cones. Growth cones are important developmental structures that play a role in neuronal survival and target selection within the developing brain. We have developed a neuronal culture system to examine the contributions of nAChRs in growth cones of neurons from the hippocampus and cortex. We are currently investigating the mechanisms driving growth and movement of axons. 30. The Evolution of Acoustic Competition in Songbirds Just as the ecological theory of niche competition applies to food resources it can apply to other resources. In this project we use niche competition to assess acoustic signals, bird songs and frog calls, to investigate if they avoid having similar signals at the same time and location which would reduce competition and improve signal detection. Results of the project will focus on the ecology and evolution of animal communication and how species interactions can influence animal communication strategies. This project will also be in conjunction with research from the National Park Service Soundscape division as recordings from Teton National Park will be used for the project. The student participating in this project will learn to identify a variety of bird songs and frog calls based on acoustic and visual cues. The student will also become proficient at using Raven a sound analysis program as well as participate in collaborative statistical techniques and meetings with scientists from the National Park Service. Finally the student will be asked to participate in writing a scientific paper based on the results of the project. 31. Novel Therapeutics for Viral Infections Currently there are no therapeutics for Rift Valley Fever Virus (RVFV) or Venezuelan Equine Encephalitis Virus (VEEV). These two viruses are transmitted by mosquito, emerging infectious diseases and biological threat agents. Students will be assigned compound(s) and will explore their toxicity and efficacy against VEEV and RVFV. Vaccine strains of the viruses (BSL-2) will be utilized for these studies. Students will learn techniques such as cell culture, viral infections, plaque assays, q-RT-PCR assays, and cell viability assays. 32. Secretome of Viral Infections Nanoparticles will be utilized as a way to capture and characterize various antigens that are released from infected cells. Rift Valley Fever Virus (RVFV) or Venezuelan Equine Encephalitis Virus (VEEV) infected cells will be studied. These two viruses are transmitted by mosquito, emerging 17 infectious diseases and biological threat agents. Vaccine strains of the viruses (BSL-2) will be utilized for these studies. Students will be responsible for standardizing the nanoparticle capture of selected viral antigens and secreted host proteins. Students will learn techniques such as cell culture, viral infections, western blot analysis, and protein purification. Students will also have the opportunity to assist with mass spectrometry analysis. 33. Design and Synthesis of Inhibitors of Protein-Protein Interactions for the Treatment of Cancers Protein-protein interactions are an attractive target for cancer treatment. However, several challenges still exist in designing a small molecule drug that interrupts protein-protein interactions. Protein-protein interactions usually involve binding at shallow surfaces between the two proteins. The inherent difficulty to bind a small molecule to a shallow protein pocket limits the ability to design a high affinity drug. Therefore, we propose to use a multivalency approach to bind multiple shallow surfaces of the protein. Incorporating a bivalent interaction has been shown to afford an exponential increase in binding affinity for compounds that would normally have very low binding affinity when interacting at one site of the protein. This strategy will be used to block oncogenic protein-protein interactions with potentials in treating cancer. 34. Synthesis and characterization of a breast homing peptide conjugate for the treatment of breast cancer Despite the tremendous successes in chemotherapy for treating cancer, chemotherapy is a very harsh treatment option for many patients. This project involves the synthesis of an organ-specific delivery system to reduce the systemic toxicity of chemotherapeutic agents. The use of a peptidic system will enable the inclusion of a reporter group that can be used to monitor the effectiveness of the delivery system in real time. The goal of this project is to show specificity a classic chemotherapeutic agent conjugated to a breast homing peptide in comparison with the chemotherapeutic agent in the absence of the breast homing peptide. 35. Investigating the Pathobiology of Lung Cancer Smoking is strongly correlated with lung cancer. However, not all smokers develop lung cancer. The population of smokers that develop COPD have an increased risk of eventually developing lung cancer. We intend to explore the association of endogenous small molecule metabolites with the development of lung cancer. This strategy has the potential to provide a diagnostic method for determining lung cancer risk in patients. 36. Using Histology to Understand Interactions between Organisms and the Environment The study of cells, tissues, organs, and organ systems is critical not only to learn about the physiology and metabolism of an organism, but to gain knowledge of that organism's relationships with other organisms (e.g., viruses, bacteria, protozans) and the impacts of environmental 18 changes that the organism experiences. Alterations in the cells and tissues from exposure to biotic and abiotic stressors can lead to disease, impairment in the organism’s vital functions, organs, or systems. The GMU Histology Laboratory supports research on non-human diseases, systematics and taxonomy, physiology, microbiology, molecular biology, or other areas, using light microscopy to learn how changes in structure affect function. Projects undertaken in the laboratory include microbial diseases of corals, effects of ingested metals in drinking water on rats and mice, reproduction in local fish species, distinguishing species of invasive gastropods, and digestion in fireworms. The student will learn histological techniques to mount tissue sections of samples from field or laboratory experiments (either a current lab project or one of their choice) and basic slide reading skills to gain an appreciation of the power of this field in organismal and environmental research. The student will also conduct literature research and prepare a short report on their observations. 37. Environmental chemical exposure and women’s health Environmental epidemiologists are interested in the study of disease in populations of people and how modifiable exposures may influence population health. Exposure to environmental chemicals within personal care products are widespread and may lead to adverse health effects. Exposure to chemicals in personal care products, diet and lifestyle factors and are not entirely understood. In particular, the chemicals of interest include phenols such as: bisphenol A and triclosan, and parabens. These chemicals have chemical structures that enable them to impact hormonal binding in experimental settings. These chemicals are included in a class of chemicals known as endocrine disruptors, which have health implications on reproductive health, cancers, and possible links to obesity and diabetes. Their possible health effects in humans are an ongoing area of research. As people are exposed to multiple chemicals and there are multiple factors that combine to cause disease processes, it is necessary to implement statistical modeling to appropriately understand the exposure-disease relationship of interest. The student will learn statistical modeling necessary for epidemiologic research and the project will focus on phenol and paraben chemical exposures, predictors of exposure (including diet and lifestyle factors) and insulin resistance in a population of premenopausal women. Insulin levels are a risk factor for metabolic syndrome and diabetes, important public health problems. 38. Novel Aspect of Anthrax Toxicity: Role of Reactive Oxygen and Nitrogen Species Generated by Bacterial Cells We recently found that B. anthracis is able to release superoxide radical and nitric oxide as toxic species killing the host cells. You will study the mechanism of the accumulation of toxic species during infection and carry out their identification using biochemical methods and mass spectroscopy. 39. Nanoparticles for Interrogation of the Infectious Disease Mechanisms 19 In collaboration with the GMU’s Center for Applied Proteomics and Molecular Medicine we develop approaches to investigate changes in the host proteome during infectious process and to deliver specific treatments using of nanoparticles. You will be involved in one of the aspects of our current research in which we use nanoparticle technology is applied to harvest the proteins of the lymph, identify the proteins by mass spectroscopy, and to deliver immunomodulating substances to the lymph nodes in the course of anthrax infection in mice. 40. Biodiversity of Virginia Spring Seeps Spring seeps are small isolated freshwater springs, typically located in undisturbed forested areas. In these springs a constant flow of groundwater comes to the surface, which quickly disappears underground again, resulting in a small wetland habitat. These spring seeps are inhabited by a wide array of invertebrate species, including molluscs, insects, and crustaceans. Because of the unexplored and isolated nature of spring seeps, the biodiversity of this habitat has yet to be thoroughly investigated. For example, which species occur in spring seeps, or which environmental variable determines the species richness, are all questions that are open for study. Students who are interested in exploring the biodiversity of spring seeps will have the opportunity to participate in fieldwork, process and sort samples, identify invertebrate species, and contribute to our understanding of the spring seep habitat. 41. Succession of Invertebrate Communities in Potomac Tributaries Over the last decades some tributaries of the Potomac River have experienced great improvements in water quality. These tributaries were once devoid of vegetation and now harbor vast beds of submerged aquatic vegetation. At the start of the spring season this vegetation is nearly absent, but grows to large abundances over the summer. During the fall season the vegetation decomposes and disappears. During its succession, this aquatic vegetation serves as habitat for many fish and invertebrates. If and how the invertebrate community responds to this vegetative succession is not fully understood. Students who are interested in exploring the ecological relationship between the succession of submerged aquatic vegetation and invertebrate communities will have the opportunity to participate in fieldwork, process and sort samples, analyze data, and contribute to our understanding of the community ecology of Potomac tributaries. 42. Insects of the George Mason University Campus 20 Habitat fragmentation plays a determining role in biological community composition. Fragmented habitats consist out of habitat-patches that differ in size and isolation. According to conventional ecological theory, the size of these patches will have an effect on the biodiversity that occur in these patches, where larger patches typically have higher levels of biodiversity. Small patches, however, may represent a unique type of habitat with special ecological functions and may therefore contain an unusual collection of species. The Fairfax campus of George Mason University represents a collection of fragmented forest patches. Numerous insect species (including beetles, ants, wasps, etc.) inhabit these forests patches, and presents a great opportunity to test the ecological effects of habitat fragmentation. Students who are interested in exploring the role of habitat fragmentation on insect communities will have the opportunity to participate in fieldwork, process and sort samples, analyze data, and contribute to our understanding of the effects of habitat fragmentation. Findings of these studies may have implications for the sustainability policy of GMU. 43. Antimicrobial Peptides Antimicrobial peptides are small peptides that act against bacteria. Students will be assigned a peptide and will explore its activity against various pathogens, including multidrug resistant bacteria. Students will also design rational variants of their peptide in order to improve its performance characteristics. Skills taught will include (1) bacterial culturing, McFarland standards, CLSI standards. (2) antimicrobial peptide assays (3) biofilm assays (4) hemolytic assays (5) cytotoxicity assays (6) advanced data analysis (IC50 plots, etc), (7) bioinformatic analysis of peptide sequence and prediction of structure. This project can accommodate more than one student; each student will study a different peptide. 44. Novel Antibiotics Novel antibiotics are critically needed. Students will be assigned candidate compounds which have potential to be antibiotics to explore their activity against various pathogens, including multidrug resistant bacteria. These may be natural products or chemically synthesized molecules. Students will also design checkerboard assays to determine synergistic or antagonistic activity. Skills taught will include (1) bacterial culturing, McFarland standards, CLSI standards. (2) MIC assays (3) biofilm assays (4) cytotoxicity assays (5) advanced data analysis (IC50 plots, etc), (6) bioinformatic analysis of bacterial genomes to identify possible drug targets (7) advanced literature searches to develop the background of the antibiotic and its potential mode of action. This project can accommodate more than one student; each student will study a different antibiotic. 45. Exploring Metabolic Changes in Very Old Nematodes 21 What happens as late stage robust adults transition into that terminal state preceding death? Do metabolic markers correlate with the phenotypic changes so characteristic of senescence? Altered locomotion, increased cellular fragility and accumulation of cellular pigmentation are characteristic of senescence in most animals, including ourselves. 46. Role of Pyk2 Activation in HIV Infection: Consult with Dr. Wu for description 47. Role of Jak/Stat PATHWAY in HIV INFECTION: Consult with Dr. Wu for description 22