-- Department of Environmental Medicine --
Program in Toxicology
Post-doctoral fellows are supported by a National Institute of Environmental Health Sciences training
grant as well as by research grants.
Consult Dr. Ned Ballatori
about the current availability of these positions.
Current Postdocs |
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Radha Aras B.S. 1995, M.S. 1996 (Maharaja Sayajirao University of Baroda, India); Ph.D. 2006 (University of Southern California) E-Mail: radha_aras@urmc.rochester.edu  |
Glial–neuronal interaction: astrocytes modulate neurodegeneration in models of Parkinson’s disease The contribution of environmental toxicants to neurodegenerative diseases has been a focus of biomedical research for many years, but much remains to be learned about how these chemicals are delivered to their site of action, how their concentrations are regulated, and how they exert their neurotoxic effects in the brain. In recent years, it has increasingly been recognized that the abundance of astrocytes, their strategic organization, and close proximity to neurons provide good opportunities for intercellular exchange of molecules between these two cell types. However, the mechanism and the extent to which astrocytes are involved in regulating the levels of neurotoxic cations and thereby affecting neurodegeneration are currently unknown. The primary goal of my project is to test the hypothesis that astrocytes play a dual role in preventing and inducing neurodegeneration by regulating the levels of toxic cations available to neurons using models of Parkinson’s disease. Advisor: Kim Tieu, Ph.D. |
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David A. Aremu B.Sc. 1990; M.Sc. 1995; M.P.H. 1998 (University of Ibadan, Nigeria); Ph.D. 2005 (Tottori University, Japan) E-Mail: david_aremu@urmc.rochester.edu  |
Characterizing the molecular mechanism of action of novel antidotes for methylmecury (MeHg) toxicity. A significant percentage of the human population is exposed to levels of methylmercury (MeHg) that, while generally considered to be quite low, may produce subtle neurological deficits, particularly in infants and children. Therefore, screening methods to help identify high-risk mothers, safe agents to initiate rapid elimination of potentially toxic levels, and nutritional supplements that may ameliorate the toxic effects of MeHg are most desired in public health. Our laboratory recently reported that N-acetylcysteine (NAC), a nontoxic N-acetyl derivative of cysteine, is remarkably effective at enhancing urinary excretion of MeHg. NAC does not alter the distribution of divalent cations, including those essential for normal physiologic functions, and thus appears to be a safe antidote. In addition, some nutrients in fish, the major source of human chronic low level exposure to MeHg, have been suggested to protect against MeHg’s neurotoxicity. This subject remains phenomenological since epidemiological results are contradictory. We are currently characterizing the molecular mechanism by which NAC accelerates the urinary excretion of MeHg, and standardizing its dosing regimen for the purpose of biomonitoring for MeHg exposure. Identifying the putative nutrients in fish as well as elucidating the possible mechanisms by which these nutrients may modify MeHg toxicity is another subject of my research. Advisor: Ned Ballatori, Ph.D. |
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Angela L. Bush, Ph.D. B.A. 2001, Georgia Southern University; Ph.D. 2007, Florida State University E-Mail: angela_bush@urmc.rochester.edu  |
Mechanisms of neuronal dysfunction and neurodegeneration in models of Parkinson’s disease and Huntington’s disease. My projects are related to two primary focuses of the lab: astroglial-neuronal interaction and mitochondrial dysfunction. In a project related to ParkinsonŐs disease, I will test the hypothesis that astrocytes modulate dopaminergic cell death induced by paraquat, a herbicide linked to parkinsonism, through the organic cation transporter-3 (OCT3). This study will be performed in mice with OCT3 deficient, co-culture models of astrocytes (from different brain regions and different developmental stages) and dopaminergic neurons, and cells stably overexpressing OCT3. My strong interest in Huntington’s disease leads me to a second project. Using our available animal and cell culture models overexpressing mutant Huntington gene, I will determine the role of mitochondrial dysfunction and evaluate the neuroprotective effects of compound(s) with high potential clinical relevance for this neurological disorders. Advisor: Kim Tieu, Ph.D. |
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Loretta L. Collins B.S. 1996, Ph.D. 2003 (University of Rochester) E-Mail: loretta_collins@urmc.rochester.edu  |
Regulation of aryl hydrocarbon receptor (AhR) function by phosphorylation. AhR is a known mediator of the toxicity of various planar aromatic hydrocarbon-based xenobiotic ligands, and has been shown to play important roles in normal development and physiology. It is crucial to understand the regulation of AhR function as a transcription factor, through which it affects cellular signaling pathways and thereby influences biological endpoints such as vascular development, hematopoiesis, and the metabolism of xenobiotic compounds. We are currently testing the hypothesis that particular N-terminal residues of AhR are phosphorylated, and that phosphorylation at these sites affects AhR transcriptional activity. Advisor: Tom Gasiewicz, Ph.D. |
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Mei Cui MD 2002 (Shanxi Medical University, China) PhD 2006 (Neurology, Fudan University, China) E-Mail: mei_cui@urmc.rochester.edu  |
Assessment of function and gene-environment interaction of mutant parkinsonian genes. In recent years several genetic mutations have been discovered in Parkinson’s disease. Our aim is to create stable cell lines with inducible over-expression of these mutated genes and their wild type counterparts. These stable cells will be used to assess how the mutated genes induce neuronal dysfunction and neurodegeneration in the presence or absence of environmental neurotoxicants. I will also determine how these diverse forms of mutations would lead to the common type of dopaminergic cell death as seen in Parkinson’s disease. Advisor: Kim Tieu, Ph.D. |
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Indika M. Edirisinghe B.Sc. 1998 (University of Delhi, India); Ph.D. 2005 (University of Peradeniya, Sri Lanka / University of California, Davis) E-Mail: indika_edirisinghe@urmc.rochester.edu  |
The role of VEGF and its receptor VEGFR2 in cigarette smoke–mediated endothelial cell dysfunction. Cigarette smoking is a risk factor of cardiovascular disease and is associated with vascular endothelial dysfunction in humans. However, the mechanism that regulates cigarette smoke-induced endothelial dysfunction is largely unknown. Vascular endothelial growth factor (VEGF) is an important regulator of vascular development. VEGF induces phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and activates downstream signaling resulting in endothelial cell migration, proliferation and survival. VEGF/VEGFR2 signaling is mediated by serine-threonine kinase (Akt), which is an important upstream kinase for endothelial nitric oxide synthase (eNOS) phosphorylation and activation that resulting in nitric oxide production in endothelial cells in response to VEGF and fluid shear stress generated by blood flow. Our project has as its underlying hypothesis that cigarette smoke exposure down regulates VEGF expression and disrupts the VEGF/VEGFR2 complex and this alteration is responsible for abnormal endothelial cell function. We are testing the hypothesis in human endothelial cells and in a mouse animal model using a variety of techniques. These include the sheer stress model, the scratch angiogenesis assay, and the matrigel assay in vitro, and the plaque assay in vivo. Advisor: Irfan Rahman, Ph.D. |
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Robert Feissner B.S. 1998 (SUNY College of Environmental Science and Forestry, Syracuse, NY) Ph.D. 2006 (Washington University at St. Louis) E-Mail: robert_feissne@urmc.rochester.edu  |
Redox modulation of cardiac mitochondrial calcium transport. It was recently discovered that cardiac mitochondria contain a ryanodine receptor (mRyR) which provides fast calcium induced calcium transport into the mitochondria and couples excitation-contraction with stimulation of TCA cycle enzymes to stimulate ATP synthesis in accordance with cardiac demand. It is known that oxidative stresses stimulate the activity of sarcoplasmic reticulum ryanodine receptors. Moreover, electron transport through the mitochondrial electron transfer chain (ETC) is a source of damaging reactive oxygen species (ROS). Current studies are testing the hypothesis that calcium transport by mRyR is modulated by cellular and mitochondrial redox compounds (eg. ROS and antioxidants). These studies will provide insight into the interplay between cardiac energy demand, the regulation of calcium transport, ROS production, and may lead to advances in therapeutics for oxidative stress-related heart disease. Advisor: Shey-Shing Sheu, Ph.D. |
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Christine Hammond B.S. 1998 (Allegheny College); Ph.D. 2004 (University of Rochester) E-Mail: christine_hammond@urmc.rochester.edu  |
Mechanisms of glutathione transport. The initial step in reduced glutathione (GSH) turnover in all mammalian cells is its transport across the plasma membrane into the extracellular space; however, the mechanisms of GSH transport are not clearly defined. GSH export is required for the delivery of its constituent amino acids to other tissues, detoxification of drugs, metals, and other reactive compounds of both endogenous and exogenous origin, protection against oxidant stress, and secretion of hepatic bile. Abnormal intracellular GSH levels that may arise from increased or decreased GSH transport have been associated with a variety of human diseases. For example, some cancerous tumors are known to have elevated GSH levels, and in diseases where increased apoptosis is observed—such as Alzheimer’s disease, Parkinson’s disease, and a variety of autoimmune disorders—low levels of intracellular GSH are observed in affected cells. Currently, our studies are focused on determining the mechanism behind GSH export during apoptosis. Our hypothesis is that MRP1, a known GSH transporter, is responsible for the drastic reduction in GSH during apoptosis. Increasing our understanding of GSH extrusion during apoptosis may help determine why certain cell populations are vulnerable to disease and help prevent or treat these diseases. Advisor: Ned Ballatori, Ph.D. |
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Hiromi Ishitobi B.A. 2001; Ph.D. 2003 (University of Tokyo) E-Mail: hiromi_ishitobi@urmc.rochester.edu  |
Neurotoxic effects of prenatal joint exposure to methylmercury and inorganic mercury. Mercury toxicity is the focus of substantial public concern. Many populations are exposed to more than one form of mercury. However, how different species of mercury act in combination is not known. The two predominant forms of mercury in our environment, methylmercury from fish, and inorganic mercury in the form of mercury vapor, are both neurotoxicants. We are investigating the effects on neurodevelopment of joint exposure during the prenatal period to these two mercury species, based on the proposition that such joint exposures have the potential to modify the developmental neurotoxicity of exposure to either species in isolation. Advisor: Bernard Weiss, Ph.D. |
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Guangbi Jin B.S. 1987 (Bethune Medical University, Changchun, China); Ph.D. 2003 (University of Tokyo) E-Mail: guangbi_jin@urmc.rochester.edu  |
Role of aryl hydrocarbon receptor (AhR) activation in antigen-presenting cell function. My research interest is the role of aryl hydrocarbon receptor (AhR) activation in antigen-presenting cell function that results in diminished clonal expansion and differentiation of influenza virus-specific CD8+ T cells. AhR is a ligand-activated transcription factor that is expressed in cells of the immune system. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is the most potent AhR agonist known, and is also a well known immune suppressant. However, the precise molecular mechanism remains unclear. We have previously shown that AhR activation by TCDD suppresses the proliferation and differentiation of influenza virus-specific CD8+ T cells. However, TCDD does not affect CD8+ T cells directly, suggesting that defects in other cells essential for activating CD8+ T cells are affected by AhR activation. I am currently testing the hypothesis that exposure to TCDD will affect the functions of dendritic cells. Advisor: B. Paige Lawrence, Ph.D. |
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Michael D. Laiosa B.S. 1997 (SUNY-Geneseo); Ph.D. 2002 (Upstate Medical University) E-Mail: michael_laiosa@urmc.rochester.edu  |
Immune system modulation by environmental toxicants. My research concerns how toxic agents in the environment interact with our genes to modulate normal biological outcomes, particularly those pertaining to the immune system, autoimmunity, and cancer. Currently, the heavy metal mercury is serving as a model to interrogate lymphocyte signaling, death and regulation of self tolerance. We have found that mercury modulates T-lymphocyte activation and apoptosis in response to antigenic challenge in vivo. Moreover, we have genetic and toxicological evidence supporting a role for the death receptor pathway CD95 in these processes. Advisor: Michael J. McCabe, Jr., Ph.D. |
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Betina J. Lew B.A. 1988 (São Paulo State University, Brasil); M.Sc. 1993 (The Hebrew University of Jerusalem, Israel); Ph.D. 2005 (São Paulo State University and Michigan State University) E-Mail: betina_lew@urmc.rochester.edu  |
Toxicology in mammary gland development and lactation I am studying the physiological, morphological, and molecular mechanisms by which pollutants alter mammary gland development during pregnancy and how these changes affect lactation in mammals. Specific focus is currently on the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin — TCDD or dioxin. This development is a complex and tightly orchestrated process involving numerous hormones, growth factors, extra cellular matrix (ECM) components, and other molecules produced locally in the mammary gland as well as in other glands and tissues. Dioxins bind and activate the aryl hydrocarbon receptor (AhR). AhR activation impairs mammary development during pregnancy, thereby blocking normal gland function during lactation. Advisor: B. Paige Lawrence, Ph.D. |
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Ravikumar Manickam B.V.Sc., 1992; M.V.Sc., 1994, Madras Veterinary College, Chennai, India; Ph.D. 2006, Roslin Institute, Edinburgh, United Kingdom E-Mail: ravikumar_manickam@urmc.rochester.edu  |
TCDD impairs mammary gland differentiation and lactogenesis 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD/Dioxin) has recently been reported to affect the mammary gland differentiation and lactogenesis in mice. However, very little is known about the cellular and molecular mechanism by which TCDD affects mammary gland differentiation and lactogenesis. Dioxin binds with high affinity to the aryl hydrocarbon receptor (AhR) and translocates to the nucleus, affecting gene expression and cellular function. The AhR and its partner the AhR nuclear translocator (ARNT) are also present in the mammary tissues. This leads to the hypothesis that AhR activation during pregnancy might disrupt the normal cellular signaling that directs pregnancy-associated mammary gland development and milk proteins gene expression, resulting in impaired mammary epithelial cells differentiation and lactation. I’m currently involved in elucidating the cellular and molecular mechanisms by which TCDD impairs milk proteins gene expression, and identifying the role of AhR in altered mammary epithelial cells differentiation and function. Advisor: B. Paige Lawrence, Ph.D. |
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Sylvia Notenboom M.S. 2000 (Katholieke University Nijmegen); Ph.D. 2005 (Radboud University, Netherlands ) E-Mail: sylvia_notenboom@urmc.rochester.edu  |
Identification and characterization of glutathione transporters. Reduced glutathione (GSH) is involved in a variety of cellular processes, including the detoxicification of endogenous and exogenous electrophiles, maintaining essential thiol status of proteins and protection against oxidative stress through radical scavenging. It is also thought to be involved in the modulation of other critical cellular processes including the regulation of gene expression, apoptosis and membrane transport of both endogenous and exogenous molecules. Disturbances in the GSH homeostasis have been implicated in the etiology and/or progression of several diseases, such as several neurological complications: HIV infection, liver disease, pulmonary disease and cancer (reviewed in Ballatori et al. Toxicol. Appl. Pharmacol. 204:238-255, 2005). It is therefore important to understand how the intracellular GSH concentration is maintained. The two major mechanisms by which the intracellular concentration of GSH is regulated are GSH biosynthesis and GSH transport. Until now GSH biosynthesis has been studied extensively. However, not much is known about the uptake or efflux of GSH. In humans only certain members of the ATP-binding cassette superfamily subfamily C have been identified as putative GSH transporters until now. The current project focuses on the identification and functional characterization of additional human genes implicated in GSH uptake and/or efflux. Advisor: Ned Ballatori, Ph.D. |
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Saravanan Rajendrasozhan B.S. 1999 (University of Madras, India); Ph.D. 2006 (Annamalai University, India) E-Mail: saravanan_rajendrasozhan@urmc.rochester.edu  |
Role of sirtuin (SIRT1) in cigarette smoke-mediated lung injury and inflammation. Chronic Obstructive Pulmonary Disease (COPD) continues to cause a heavy health and economic burden both in the United States and around the world. Cigarette smoke is a important trigger of oxidative stress and inflammation in COPD by a mechanism mediated via pro-inflammatory gene transcription. Histone acetylatases are the key regulators of the specificity and duration of this gene transcription. In our lab, we found out that class III histone deacetylases (sirtuin) were decreased in reasponse to cigarette smoke exposure both in vitro and in vivo. This was correlated with the increased release of pro-inflammatory cytokines. My research concerns how sirtuin is decreased in response to cigarette smoke exposure and how it regulates the pro-inflammatory cytokine release. Moreover, we are investigating whether regulation of sirtuin can control the progression of inflammation/COPD, which is measured both in vitro, with human airway epithelial cells and macrophages, and in vivo, with genetic sirtuin knockout mice. Advisor: Irfan Rahman, Ph.D. |
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Amber Rinderknecht B.A. 1998 (Emory University ); Ph.D. 2005 (University of California, Irvine) E-Mail: amber_rinderknecht@urmc.rochester.edu  |
Translocation and toxicological effects of inhaled nanoparticles. Nanotechnology is a burgeoning field and includes the use of nanoparticles for biomedical, industrial, and consumer applications. Because of the large surface area and vast underlying vasculature offered by the lung epithelium, particle accessibility to systemic circulation following pulmonary exposure generates great concern. However, little focus has been given to the toxicological and inflammatory responses that result from exposure to these nanoengineered particles. My research studies how particle surface-functionalization, size and dose greatly influence sight-specific inflammation, whole-body translocation, and cardiovascular injury after exposure through the respiratory system. Advisor: Günter Oberdörster, Ph.D. |
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Isaac Kirubakaran Sundar B.Sc. 2000 (University of Madras, India); M.Sc. 2002, (Periyar University, India); Ph.D. 2007 (Pondicherry University, India) E-Mail: isaac_sundar@urmc.rochester.edu  |
Epigenetic regulation of lung inflammation. Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, deacetylation and methylation. Aging, diet, environmental exposures and other stresses can cause epigenetic alterations, resulting in cancer or other chronic inflammatory diseases, such as COPD, asthma, and pulmonary fibrosis. The aim of our research is to determine the molecular mechanisms of epigenetic alterations via IKKalpha and MAP kinase pathways in response to environmental oxidants, such as cigarette smoke (CS). Understanding the intracellular signaling pathways involved in epigenetic regulation of lung inflammation will allow us to identify therapeutic targets for many chronic inflammatory lung diseases and cancer. Advisor: Irfan Rahman, Ph.D. |
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Hongwei Yao Master of Medicine 2000; Ph.D. 2003 (Zhejiang University, China) E-Mail: hongwei_yao@urmc.rochester.edu  |
Role of NADPH oxidase in cigarette smoke–induced inflammation in mice. Increased oxidative stress, due to either inhaled or endogenously-generated oxidants, occurs in cigarette smoke-induced lung injury and inflammation. NADPH oxidase is the main cellular source of reactive oxygen species (ROS) in mononuclear and granulocytic leukocytes. It is composed of five subunits, p40phox (phox for phagocytic oxidase), p47phox, p67phox, p22phox, and gp91phox. We hypothesized that targeted ablation of components of NADPH oxidase (p47phox-/- and gp91phox-/-) would protect lungs against detrimental effects of cigarette smoke (CS) by not generating endogenous ROS. To test the hypothesis, we are studying the effects of CS (acute and chronic exposures) and assessing the oxidative and inflammatory responses in lungs of these mice. Advisor: Irfan Rahman, Ph.D. |