-- Department of Environmental Medicine --
Program in Toxicology
Postdoctoral Fellows
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.
Gnanapragasam Arunachalam
B.S 1999, Ph.D. 2007; University of Madras,
Chennai, India
E-mail:
Gnanapragasam_Arunachalam@urmc.rochester.edu
Cigarette smoke and endothelial dysfunction.
Impairment of endothelial function is the hallmark in pathogenesis
of various pulmonary and cardiovascular diseases (CVD). Endothelial nitric oxide
(NO) is produced by endothelial nitric oxide synthase (eNOS), which is known to
regulate vascular homeostasis. SIRT1 is a member of a highly conserved gene
family (sirtuins) encoding NAD(+)-dependent deacetylases which has been
shown to promote endothelial-dependent vasodilation by targeting eNOS for
its deacetylation leading to enhance NO production. Likewise, blocking SIRT1 in endothelial cells
will decrease the NO bioavailability and thereby
inhibit endothelium-dependent vasorelaxation.
My research is focused on determining the
molecular mechanisms of SIRT1 mediated eNOS regulation in endothelial cells
and VEGF mediated endothelial dysfunction in response to cigarette smoke.
Thus, determining the SIRT1-eNOS signaling pathway in endothelial dysfunction
in response to cigarette smoke will provide mechanism underlying
the pathogenesis of pulmonary and CVD.
Advisor: Irfan Rahman, Ph.D.
Simona Bancos
B.S. 1998; M.S. 1999 Babes-Bolyai University, Cluj-Napoca, Romania;
Ph.D. 2003, Biological Research Center, Szeged Hungary.
E-mail: simona_bancos@urmc.rochester.edu
Role of cyclooxygenases in B cell function.
Some environmental toxicants such as cigarette smoke, diesel
exhausts and dioxin influence cells to alter their synthesis of small lipid
mediators called prostaglandins (PG). PGs are a group of bioactive lipids
playing important roles in inflammation, angiogenesis, cancer and atherosclerosis.
They are generated through the cyclooxygenase activity, which catalyze
the conversion of arachidonic acid to PGG2 and then PGH2. There are two
types of cyclooxygenases. The constitutive Cox-1 is involved in homeostasis
of various physiological functions, while Cox-2 is dramatically upregulated
during inflammation and cancer.
We are studying the mechanism how selected
toxicants influence the immune
system, including B lymphocytes. B lymphocytes, when activated, express
Cox-2 and this is important for optimal antibody production. Chronic
upregulation of B cell Cox-2 can lead to abnormal antibody production
or to malignancy.
Advisor: Richard Phipps, Ph.D.
Sangwoon Chung
B.S. 1999, M.Sc. 2003 (Pusan National University, South Korea);
Ph.D. 2007 (Kanazawa University, Japan).
E-Mail: sang_chung@urmc.rochester.edu
Role of NIK in NF-κB signaling and chromatin remodeling
Activation of nuclear factor (NF)-κB/Rel family plays
a pivotal role in inflammatory response which is controlled by NF-κB-inducing
kinase (NIK). NIK forms a complex with and phosphorylates IκB kinase (IKK)1
and IKK2, subsequently leading to the phosphorylation of IκB and translocation
of NF-κB to the nucleus. NF-κB activation can be controlled by at two
separate pathways, the canonical and non-canonical pathways, which are
activated by distinct stimuli via distinct IKK complexes. Among these
pathways, non-canonical pathway stimulates a complex of NIK and IKKα,
resulting in the phosphorylation-coupled proteolysis of 100 κDa NF-κB2
to form
the activated 52 kDa NF-κB2-RelB complex.
We hypothesized that cigarette smoke,
oxidants and aldehydes via NIK, activate IKK1 which, though interaction
with CREP-binding protein (CBP), is able to induce histone H3
acetylation-chromatin modifications on pro-inflammatory promoters.
This acetylation allows the RelA/p65 to bind DNA and transcribe
pro-inflammatory cytokines. Also, we are investigating whether
RelB pathway contribute to histone acetylation and chromatin
modifications in a variety of cells, e.g. lymphoid B & T cells,
macrophages and lung epithelial cells by cigarette smoke.
Advisor: Irfan Rahman, Ph.D.
Mei Cui
M.D. 2002 (Shanxi Medical University, China)
Ph.D. 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.
Morton Ehrenberg
B.S. 2000 (Cornell University); Ph.D. 2008 (University of Rochester)
E-Mail: morton_ehrenberg@urmc.rochester.edu
Proteomics of nanoparticle toxicology.
Nanoparticles (NP) have features similar in size to the simplest components of living systems. This makes NP attractive for many diagnostic and therapeutic technologies and also raises concern that unintended health consequences may result from use and manufacturing of products incorporating NP.
Studies of ambient and
engineered particles have shown greater toxicity of nanosized particles compared to larger ones, however the mechanisms remain poorly understood. This work is directed at elucidating a mechanisms for NP health effects. It is focused on particle interactions within rat lung, a system that has is used extensively by our research group
to study inhalation toxicology, including NP.
Characterization of the protein environment within the rat lung will be followed by detailed analysis of the adsorbtive interactions of these proteins at particle surfaces. Combined with toxiclological data, these investigations will provide insight into the mechanisms of NP interactions with living systems.
Advisors: Drs. Alison Elder and Alan Friedman.
Matthew Giannandrea
B.A. 1996 (Gonzaga University);
Ph.D. 2009 (University of Rochester)
E-Mail: matthew_giannandrea@urmc.rochester.edu
Neonatal oxygen supplementation and its effects on the immune response to respiratory viral infections.
Infants that are born premature and with a very low birth weight often experience respiratory distress and require supplementary oxygen in order to survive. However, this treatment alters the normal development of the lung and results in decreased lung function and increased incidence of respiratory infections.
Using a mouse model where newborn pups are exposed to high levels of oxygen, I will be studying how oxygen supplementation at birth changes how the immune system responds to infection by the influenza A virus. Our initial focus is on CD8+ T-cells, which are important for viral clearance.
Advisor: B. Paige Lawrence, Ph.D.
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.
Jae-woong Hwang
B.S. 2000; Ph.D. 2008 (Seoul National University, South Korea).
E-Mail: jae-woong_hwang@URMC.rochester.edu
Role of SIRT1 in cigarette smoke-induced autophagy.
Human sirtuin (SIRT1) is essential for maintaining silent
chromatin via the deacetylation of proteins including non-histones and
histones. SIRT1 plays an important role in a wide variety of processes,
including stress resistance, metabolism, apoptosis, senescence, differentiation,
and aging. SIRT1 regulates cigarette smoke-induced inflammation, and
cigarette smoke causes oxidative stress which is now known to be responsible
for triggering inflammatory events and apoptosis in the lungs of
smokers/COPD patients.
Oxidative stress is implicated in autophagy
and SIRT1 has a role in regulation of autophagy. Autophagy is a general
term for the degradation of cytoplasmic components within lysosomes and
is important for various physiological and pathophysiological processes.
My research interest is to study the role of SIRT1 in role of cigarette
smoke-induced autophagic cell death in lung cells,
and its relevance to human COPD.
Advisor: Irfan Rahman, Ph.D.
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.
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.
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.
Ramil Sapinoro
B.S. 2001 (Pacific University);
M.S. 2004, Ph.D. 2008 (University of Rochester).
E-Mail: Ramil_sapinoro@urmc.rochester.edu
Mechanisms of lung inflammation and fibrosis and
the role of the peroxisome-proliferator-activated receptors (PPARs) in these diseases.
The pathogenic mechanisms characterizing pulmonary
fibrosis, a critical component in an array of pulmonary disorders, are poorly
understood, but the cytokine TGFb appears to be a critical mediator in
the maintenance of the pro-fibrotic phenotype. The lipid-activated
transcription factor/nuclear receptor known as PPARg has recently
emerged as a key regulator in the processes related to fibrogenesis.
Naturally occurring and synthetic ligands of PPARg have the ability
to act as anti-fibrotic agents, reducing the fibrotic effects of
TGFb and blocking the differentiation of fibroblasts to
myofibroblasts (effector cells of fibrosis).
My research
will explore the role of the PPARg pathway as a significant
mediator of pulmonary fibrosis in an in vivo mouse model
using PPARg knock-out mice and their wild-type counterparts,
and studying the effects of PPARg agonists as efficacious
agents in reducing pulmonary fibrosis.
Advisor: Patricis Sime, M.D.
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.
Collynn Woeller
B.Sc. 2001 (SUNY Geneseo);
PhD. 2007 (Cornell University)
E-Mail: collynn_woeller@urmc.rochester.edu
Environmental and genetic factors that modulate PPARγ function in inflammation and other biological processes.
The fatty acid binding protein, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that functions in numerous biological pathologies and processes including: inflammation, diabetes, wound healing, lipid metabolism, cellular differentiation, and apoptosis. PPARγ is most well studied for its role as a “master regulator” of adipogenesis. However, PPARγ’s role in mediating anti-inflammatory responses is increasingly being recognized as a central regulatory mechanism. PPARγ ligands come from a wide variety of sources including: endogenously derived fatty acids, dietary nutrients, environmental compounds and pharmaceutical drugs. Interestingly, PPARγ ligands are very diverse in their chemical structure.
The thiazolidinediones are a class of anti-diabetic drugs that function as PPARγ agonists and have recently shown promise as anti-inflammatory agents. The nutritionally acquired lipid linoleic acid and some of its derivatives are also PPARγ ligands that have demonstrated anti-inflammatory effects. 15-deoxy-prostaglandin J2 (15d-PGJ2) is an endogenously synthesized PPARγ ligand and affects inflammation, platelet production (thrombopoiesis), apoptosis and fibroblast cell differentiation. Although many consequences of PPARγ activation are known to be induced by its role as a transcriptional activator, other functions (e.g. transrepression of inflammatory genes) are also increasingly being recognized as important in PPARγ -mediated pathways.
My project will focus on elucidating the molecular mechanisms whereby environmental or metabolically derived PPARγ ligands contribute to PPARγ pathway activation and regulation in several model systems including: thyroid eye disease, platelet function, lung tissue scarring and B lymphocyte function.
Advisor: Richard Phipps, Ph.D.
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.
Revised October 12, 2009 (vgl)
|
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.
|
|
Gnanapragasam Arunachalam B.S 1999, Ph.D. 2007; University of Madras, Chennai, India E-mail: Gnanapragasam_Arunachalam@urmc.rochester.edu |
Cigarette smoke and endothelial dysfunction. Impairment of endothelial function is the hallmark in pathogenesis of various pulmonary and cardiovascular diseases (CVD). Endothelial nitric oxide (NO) is produced by endothelial nitric oxide synthase (eNOS), which is known to regulate vascular homeostasis. SIRT1 is a member of a highly conserved gene family (sirtuins) encoding NAD(+)-dependent deacetylases which has been shown to promote endothelial-dependent vasodilation by targeting eNOS for its deacetylation leading to enhance NO production. Likewise, blocking SIRT1 in endothelial cells will decrease the NO bioavailability and thereby inhibit endothelium-dependent vasorelaxation. My research is focused on determining the molecular mechanisms of SIRT1 mediated eNOS regulation in endothelial cells and VEGF mediated endothelial dysfunction in response to cigarette smoke. Thus, determining the SIRT1-eNOS signaling pathway in endothelial dysfunction in response to cigarette smoke will provide mechanism underlying the pathogenesis of pulmonary and CVD. Advisor: Irfan Rahman, Ph.D. |
B.S. 1998; M.S. 1999 Babes-Bolyai University, Cluj-Napoca, Romania; Ph.D. 2003, Biological Research Center, Szeged Hungary.
E-mail: simona_bancos@urmc.rochester.edu
Role of cyclooxygenases in B cell function.
Some environmental toxicants such as cigarette smoke, diesel exhausts and dioxin influence cells to alter their synthesis of small lipid mediators called prostaglandins (PG). PGs are a group of bioactive lipids playing important roles in inflammation, angiogenesis, cancer and atherosclerosis. They are generated through the cyclooxygenase activity, which catalyze the conversion of arachidonic acid to PGG2 and then PGH2. There are two types of cyclooxygenases. The constitutive Cox-1 is involved in homeostasis of various physiological functions, while Cox-2 is dramatically upregulated during inflammation and cancer.
We are studying the mechanism how selected toxicants influence the immune system, including B lymphocytes. B lymphocytes, when activated, express Cox-2 and this is important for optimal antibody production. Chronic upregulation of B cell Cox-2 can lead to abnormal antibody production or to malignancy.
Advisor: Richard Phipps, Ph.D.
|
Sangwoon Chung B.S. 1999, M.Sc. 2003 (Pusan National University, South Korea); Ph.D. 2007 (Kanazawa University, Japan). E-Mail: sang_chung@urmc.rochester.edu |
Role of NIK in NF-κB signaling and chromatin remodeling Activation of nuclear factor (NF)-κB/Rel family plays a pivotal role in inflammatory response which is controlled by NF-κB-inducing kinase (NIK). NIK forms a complex with and phosphorylates IκB kinase (IKK)1 and IKK2, subsequently leading to the phosphorylation of IκB and translocation of NF-κB to the nucleus. NF-κB activation can be controlled by at two separate pathways, the canonical and non-canonical pathways, which are activated by distinct stimuli via distinct IKK complexes. Among these pathways, non-canonical pathway stimulates a complex of NIK and IKKα, resulting in the phosphorylation-coupled proteolysis of 100 κDa NF-κB2 to form the activated 52 kDa NF-κB2-RelB complex. We hypothesized that cigarette smoke, oxidants and aldehydes via NIK, activate IKK1 which, though interaction with CREP-binding protein (CBP), is able to induce histone H3 acetylation-chromatin modifications on pro-inflammatory promoters. This acetylation allows the RelA/p65 to bind DNA and transcribe pro-inflammatory cytokines. Also, we are investigating whether RelB pathway contribute to histone acetylation and chromatin modifications in a variety of cells, e.g. lymphoid B & T cells, macrophages and lung epithelial cells by cigarette smoke. Advisor: Irfan Rahman, Ph.D. |
|
Mei Cui M.D. 2002 (Shanxi Medical University, China) Ph.D. 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. |
|
Morton Ehrenberg B.S. 2000 (Cornell University); Ph.D. 2008 (University of Rochester) E-Mail: morton_ehrenberg@urmc.rochester.edu |
Proteomics of nanoparticle toxicology. Nanoparticles (NP) have features similar in size to the simplest components of living systems. This makes NP attractive for many diagnostic and therapeutic technologies and also raises concern that unintended health consequences may result from use and manufacturing of products incorporating NP. Studies of ambient and engineered particles have shown greater toxicity of nanosized particles compared to larger ones, however the mechanisms remain poorly understood. This work is directed at elucidating a mechanisms for NP health effects. It is focused on particle interactions within rat lung, a system that has is used extensively by our research group to study inhalation toxicology, including NP. Characterization of the protein environment within the rat lung will be followed by detailed analysis of the adsorbtive interactions of these proteins at particle surfaces. Combined with toxiclological data, these investigations will provide insight into the mechanisms of NP interactions with living systems. Advisors: Drs. Alison Elder and Alan Friedman. |
|
Matthew Giannandrea B.A. 1996 (Gonzaga University); Ph.D. 2009 (University of Rochester) E-Mail: matthew_giannandrea@urmc.rochester.edu |
Neonatal oxygen supplementation and its effects on the immune response to respiratory viral infections. Infants that are born premature and with a very low birth weight often experience respiratory distress and require supplementary oxygen in order to survive. However, this treatment alters the normal development of the lung and results in decreased lung function and increased incidence of respiratory infections. Using a mouse model where newborn pups are exposed to high levels of oxygen, I will be studying how oxygen supplementation at birth changes how the immune system responds to infection by the influenza A virus. Our initial focus is on CD8+ T-cells, which are important for viral clearance. Advisor: B. Paige Lawrence, Ph.D. |
|
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. |
|
Jae-woong Hwang B.S. 2000; Ph.D. 2008 (Seoul National University, South Korea). E-Mail: jae-woong_hwang@URMC.rochester.edu |
Role of SIRT1 in cigarette smoke-induced autophagy. Human sirtuin (SIRT1) is essential for maintaining silent chromatin via the deacetylation of proteins including non-histones and histones. SIRT1 plays an important role in a wide variety of processes, including stress resistance, metabolism, apoptosis, senescence, differentiation, and aging. SIRT1 regulates cigarette smoke-induced inflammation, and cigarette smoke causes oxidative stress which is now known to be responsible for triggering inflammatory events and apoptosis in the lungs of smokers/COPD patients. Oxidative stress is implicated in autophagy and SIRT1 has a role in regulation of autophagy. Autophagy is a general term for the degradation of cytoplasmic components within lysosomes and is important for various physiological and pathophysiological processes. My research interest is to study the role of SIRT1 in role of cigarette smoke-induced autophagic cell death in lung cells, and its relevance to human COPD. Advisor: Irfan Rahman, Ph.D. |
|
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. |
|
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. |
|
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. |
|
Ramil Sapinoro
B.S. 2001 (Pacific University); M.S. 2004, Ph.D. 2008 (University of Rochester). E-Mail: Ramil_sapinoro@urmc.rochester.edu |
Mechanisms of lung inflammation and fibrosis and the role of the peroxisome-proliferator-activated receptors (PPARs) in these diseases. The pathogenic mechanisms characterizing pulmonary fibrosis, a critical component in an array of pulmonary disorders, are poorly understood, but the cytokine TGFb appears to be a critical mediator in the maintenance of the pro-fibrotic phenotype. The lipid-activated transcription factor/nuclear receptor known as PPARg has recently emerged as a key regulator in the processes related to fibrogenesis. Naturally occurring and synthetic ligands of PPARg have the ability to act as anti-fibrotic agents, reducing the fibrotic effects of TGFb and blocking the differentiation of fibroblasts to myofibroblasts (effector cells of fibrosis). My research will explore the role of the PPARg pathway as a significant mediator of pulmonary fibrosis in an in vivo mouse model using PPARg knock-out mice and their wild-type counterparts, and studying the effects of PPARg agonists as efficacious agents in reducing pulmonary fibrosis. Advisor: Patricis Sime, M.D. |
|
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. |
|
Collynn Woeller B.Sc. 2001 (SUNY Geneseo); PhD. 2007 (Cornell University) E-Mail: collynn_woeller@urmc.rochester.edu |
Environmental and genetic factors that modulate PPARγ function in inflammation and other biological processes. The fatty acid binding protein, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that functions in numerous biological pathologies and processes including: inflammation, diabetes, wound healing, lipid metabolism, cellular differentiation, and apoptosis. PPARγ is most well studied for its role as a “master regulator” of adipogenesis. However, PPARγ’s role in mediating anti-inflammatory responses is increasingly being recognized as a central regulatory mechanism. PPARγ ligands come from a wide variety of sources including: endogenously derived fatty acids, dietary nutrients, environmental compounds and pharmaceutical drugs. Interestingly, PPARγ ligands are very diverse in their chemical structure. The thiazolidinediones are a class of anti-diabetic drugs that function as PPARγ agonists and have recently shown promise as anti-inflammatory agents. The nutritionally acquired lipid linoleic acid and some of its derivatives are also PPARγ ligands that have demonstrated anti-inflammatory effects. 15-deoxy-prostaglandin J2 (15d-PGJ2) is an endogenously synthesized PPARγ ligand and affects inflammation, platelet production (thrombopoiesis), apoptosis and fibroblast cell differentiation. Although many consequences of PPARγ activation are known to be induced by its role as a transcriptional activator, other functions (e.g. transrepression of inflammatory genes) are also increasingly being recognized as important in PPARγ -mediated pathways. My project will focus on elucidating the molecular mechanisms whereby environmental or metabolically derived PPARγ ligands contribute to PPARγ pathway activation and regulation in several model systems including: thyroid eye disease, platelet function, lung tissue scarring and B lymphocyte function. Advisor: Richard Phipps, Ph.D. |
|
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. |