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Research Focus Groups
The science research within the NYU NIEHS Center was reorganized in 2009 into interdisciplinary Focus Groups. As shown in the Table below, the Center research is currently organized into 4 Research Focus Groups (Early Detection and Prevention, Metals, Particulate Matter, and Environment and Susceptibility to Disease). This provides Center members a fluid research structure which encourages new and changing interactions across various research disciplines (e.g., epidemiology, controlled exposure studies, and biomarker development).
Each Focus Group has 2 co-leaders to enhance interdisciplinary collaborations and to promote innovation. One co-leader primarily directs laboratory studies while the other co-leader is involved with exposure assessment and translational human effect studies. Even though this is a very new initiative in our Center (since 2009), a number of collaborations and new research areas have developed as a result of this very important Center activity.
Early Detection and Prevention Focus Group - Co-Leaders: Wei Dai, PhD and Ann Zelenuich-Jacquotte, PhD
Metals Focus Group - Co-Leaders: Max Costa, PhD and George Thurston, DSc
Ambient Air Particulate Matter Focus Group - Co-Leaders: Morton Lippmann, PhD and Lung Chi Chen, PhD
Susceptibility to Environmental Disease Focus Group - Co-Leaders: Richard Hayes, PhD and Terry Gordon, PhD
Table 1. NYU Center of
Excellence Research Interaction Focus Groups
The overall unifying theme of this Focus Group is to engender collaborative research that will reduce the incidence of and mortality from cancer through chemoprevention and early detection. Long term goals are to: 1) identify novel targets for prevention of cancer development, invasion and metastasis; 2) discover natural and/or synthetic compounds for effective prevention of malignant transformation and cancer progression; and 3) develop specific and sensitive biomarkers and/or methodologies for early cancer detection.
One of the most cost-effective and desirable strategies for cancer intervention is prevention. During the past several decades, scientists in conjunction with clinicians have explored the cancer chemoprevention approach by identifying and characterizing natural, synthetic, or biologic chemical agents to prevent, reverse, or suppress cancer development and progression. Many of the tested agents have exhibited excellent properties in cancer prevention clinical trials in high-risk populations, thereby validating chemoprevention as a rational and appealing strategy. Several collaborative research projects in the Focus Group center on the early detection of malignancies as well as on the discovery and development of novel and effective chemopreventive compounds for cancer intervention.
Our collective efforts have yielded a substantial body of knowledge about cancer prevention and early detection. This Focus Group emphasizes interdisciplinary and multi-disciplinary approaches to the identification and validation of novel chemopreventive compounds and seeks to develop new biomarkers for early detection of cancer. To make use of the diverse expertise in the Focus Group, we focus on fostering collaborations among the members.
Highlights of Collaboration
Animal Models for Cancer Chemoprevention. Dr. Dai, in conjunction with Dr. Costa, has focused on the elucidation of mechanisms by which genomic instability is suppressed during cell division. Dr. Dai and his collaborators have produced two lines of genetically-modified mouse strains that are deficient in either BubR1 or PLK3 genes that are important for maintaining genome stability.
Biomarkers for early detection of lung cancer. Dr. Rom leads the NYU Lung Cancer Biomarker Center which has allowed the study of biomarkers in a population of high risk smokers and has accrued a screening cohort of over 1100 high risk smokers and a rule/out lung cancer cohort. With Dr. Pass (Thoracic Surgery), serum and tumor samples have been collected from subjects at high risk for lung cancer. Dr. Tang, in conjunction with Dr. Rom, has been developing a GeneChip that specifically detects mutations of common oncogenes and tumor suppressor genes. Using this chip, they determined mutations in 14 genes in lung tumor tissues from 28 patients and matching marginal tissues from 22 of these patients.
Biomarker validation and development. In collaboration with Drs. Tang, L. Chen and Costa, Dr. Qu has identified and validated several biomarkers including gene polymorphisms, chromosome aberrations detected by both conventional and FISH assays, DNA adducts, and metabolites in recruited subjects, including both healthy and poisoned workers after exposure to polycyclic aromatic hydrocarbons , benzene, or chromium. In conjunction with Dr. Hayes, Dr. Ahn has focused on the development of new biomarkers for early detection of prostate cancer. Genome wide association studies have revealed that prostate cancer risk is related to genetic variants in MSMB, the gene coding for the prostate secretory protein (PSP94).
CAPE and its mechanism of action. During the past several years, Dr. Frenkel in collaboration with Drs. Rossman and X. Huang, has characterized chemopreventive properties of caffeic acid phenethyl ester (CAPE) by demonstrating that CAPE is also very effective in inhibiting neutrophil activation, suppressing arsenite-mediated human cell transformation, and counteracting arsenite-mediated changes in gene expression. In collaboration with Dr. Klein, Dr. Frenkel has demonstrated that, although innocuous to normal mammary cells, CAPE inhibits growth of breast cancer cells, both ER-positive and -negative, while down-regulating expression of proliferation and anti-apoptotic genes.
This focus group seeks to foster interdisciplinary collaborations that will investigate the exposures and health effects of metals in the environment. Heavy metals represent persistent environmental contaminants that can never be destroyed. The burning of fossil fuels has created substantial air pollution containing toxic and carcinogenic heavy metals such as nickel, chromate, cadmium and mercury. In addition, metals are utilized extensively in industry for making stainless steel, chrome plating, and anti-rust uses (Cr), to preserve wood (chromated copper arsenate [CCA]), and in paints and pigments (lead, titanium). Thus, there is abundant ground water contamination with heavy metals and they are present at high concentrations in many Superfund sites. This pollution offers numerous opportunities for humans to be exposed to toxic and carcinogenic metals. Dr. Costa, co-leader of this Focus Group, has been conducting laboratory studies concerning nickel, chromium and arsenic carcinogenesis for over 30 years. George Thurston, Focus Group co-leader, is interested in assessing the adverse effects of heavy metals that are present in particulate matter (PM) air pollution through his large cohort studies. The Focus Group meetings have consisted of each investigator speaking for 10-20 minutes about a recent grant application or research project they are developing, leading to inputs and collaborations. For example, Dr. Lung Chi Chen has a strong interest in understanding how PM air pollution causes atherosclerosis and in discussing his animal model studies of mice exposed chronically to nickel nanoparticles, a collaboration was established with Dr. Costa to study global histone modifications in the lungs of control and nickel-treated mice. Drs. Chen and Qu also have a project investigating cardiovascular disease in a Chinese population with an environmental exposure to nickel. This discussion led to collaboration between Drs. Qu and Costa in which Dr. Qu traveled to China and obtained white blood cells from controls and nickel-exposed workers. Dr. Costa will perform ChIP-Seq and gene expression analysis on these samples using antibodies against H3K4 trimethylation. This collaboration and the funding of a Pilot Project from the Center have resulted in the funding of a competitive revision of Dr. Costa's nickel carcinogenesis grant. This Focus Group has also led to a number of other interactions, for example a collaboration between Drs. Dai and Costa on the regulation of the stability and activity of nickel-induced Hypoxia inducible factor 1α (HIF-1a) by Polo-like kinase 3 and on the characterization of post-translational modifications of histones during the cell cycle after exposure to arsenic or chromium. As the result of these collaborations fostered by the Center, one research paper was published in Cancer Research last year, and a review paper is in press in Cell Cycle. The Focus Group has also lead to collaborations between Drs. Chuanshu Huang's and Costa's lab to investigate the effects of nickel in activating JNK, which phosphorylates HDAC-6 to activate the enzyme that then deacetylates HSP-90 and activates this chaperone to allow Hypoxia inducible factor translation. A paper on this work is currently in press in Cancer Research.
Highlights of Collaboration
- Drs. Chen and Lippmann, in collaboration with Drs. Sun and Rajagopalan of Ohio State University, have investigated the cardiovascular effects of ambient particle pollution focusing on the contributions of transition metals resulting from combustion of fossil fuels.
- Drs. Chen and Gordon have investigated the long-term pulmonary, cardiovascular and central nervous system effects of inhaled Cu, Ti, C and Ni nanoparticles.
- Dr. M Cohen, along with Drs. Chen and Zelikoff, are performing a NIOSH/CDC-funded (4-yr) study in a rat inhalation model to determine the toxicities of WTC dusts and how select physicochemical properties of the dusts (including content of specific metals) contribute to the underlying increased incidence of airway hyper-responsiveness and the development of sarcoid-like granulomatous pulmonary disease (SLGPD) that have been documented in exposed First Responders.
- Drs. M. Cohen and H. Chen have begun a collaboration which examines the role of HIF-1α-related alterations in histone modification in the induction of pulmonary immunomodulation caused by metals that are commonly present in urban air pollution.
- Metallic components of inhaled particles are responsible for a number of environmentally-related diseases. Because the adverse effects of inhaled particles are size-dependent, Drs. LC Chen and Gordon have compared the adverse pulmonary effects of inhaled nanoparticles of several metals including nickel, copper, and zinc. In similar experiments, Drs. LC Chen and Gordon have collaborated with Dr. Wirgin to compare the early life-stage toxicity of several metal nanoparticles in 2 environmentally relevant species of fish.
- Dr. Gordon has closely examined the role of genetics in the adverse pulmonary and immune responses to inhaled beryllium and, in translational studies with Dr. Grunig and investigators at the University of Colorado, is comparing the specificity of 3 different approaches to biomarker development for beryllium sensitization and chronic beryllium disease in an animal model.
- Exposure to ambient fine particulate matter (PM2.5) has been associated with increased risk of cardiovascular diseases (CVD). However, the underlying mechanism(s) and major component(s) responsible for PM2.5 associated CVD are still poorly understood. Drs. Qu, LC Chen, and Ito have conducted a human population study to test the hypothesis that nickel plays important roles in PM2.5 associated CVD.
- It has been observed in Dr. Costa's lab that in vitro exposure to nickel induced histone modifications including H3K4 trimethylation and H3K9 dimethylation. These epigenetic changes have been considered as an important mechanism of nickel associated lung cancer. To test this cutting edge hypothesis in humans, Drs. Costa and Qu are conducting a translational study among nickel refinery workers identified in China.
Ambient Air Particulate Matter Focus Group (PMFG)
Mort Lippmann and Lung-Chi Chen, Co-leaders
Particulate matter (PM) in community air is associated with excess mortality and morbidity. There are tens of thousands of premature deaths in the U.S., each year, mostly due to cardiovascular causes, attributable to exposure to PM2.5, which refers to the mass concentration of PM with aerodynamic diameter below 2.5 um. The associations are stronger than those for ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO). PM2.5 is a complex mixture of particles that vary greatly in chemical composition and particle structure. There is a need to identify the most toxic chemical components, and their sources, so that interventions can target on those components for primary prevention. Identification of the most toxic components will also permit the development of strategies for exposure avoidance and prophylaxis for people especially sensitive (secondary prevention). We are focused on identifying the most biologically active PM components: 1) on the multi-organ effects and underlying biological mechanisms of subchronic inhalation exposures of mice to concentrated ambient air PM2.5; 2) the acute effects of ultrafine, fine, and coarse PM administered in vivo to mice by intra-tracheal (IT) aspiration, and to lung epithelial and brain cells in vitro; 3) on the short-term mortality and morbidity responses of urban populations to peak concentrations; 4) on long-term exposures of urban populations on reductions in life-expectancy; 5) in utero effects of cigarette smoke; 6) the effects of nanoparticle exposure in utero and the effects of CAPs on birth outcomes; 7) an asthma clinic population and PM effects on cells (IL-13) - and examining SNPs in a large cohort; 8) a study PM's effect on epigenetic control of IL-13; and 9) integrated focus on multi-pollutant atmospheres.
Another research area of active interest to this Focus Group is nanotechnology. There is rapidly growing interest in nanotechnology for various medical and technological applications, such as imaging, drug delivery devices, cosmetics, and electronics, although humans have been exposed to nano-sized particles (i.e., particles with diameters < 100nm), either naturally occurring (e.g. viruses and condensation aerosols from forest fires) or from anthropogenic sources (e.g., condensation aerosol effluents from power plants, welding fumes). Considering the rapid growth of nanotechnology, it is essential to identify, quantify, and manage potential health risks related to NPs exposure. Research project grants in this emerging area in recent years have been focused on in vitro responses); physical and chemical characterization, inhalation toxicology; and the effect of maternal nanoparticle exposure on fetal health.
Highlights of Collaboration
- Drs. Lippmann, Chen and Odin, and Drs. Rajagopalan and Sun at Ohio State University, on the multi-organ effects and underlying biological mechanisms of subchronic inhalation exposures of mice to concentrated ambient air PM2.5 in Tuxedo, NY, and in Manhattan, with Dr. Luchtel of the Univ. of Washington in Seattle, WA, with Dr. Kleinman of UC Irvine (UCI), and with Dr. Harkema of Michigan State Univ. in E. Lansing, MI.
- Drs. Gordon and Lippmann on the acute effects of ultrafine, fine, and coarse PM administered in vivo to mice by intra-tracheal (IT) aspiration, and to lung epithelial and brain cells in vitro.
- Drs. Ito and Thurston, with Dr. Ross of Zev Ross Assoc., on the short-term mortality and morbidity responses of urban populations to peak concentrations.
- Drs. Thurston and Ito, with Dr. Burnett of Health Canada and Dr. Krewski of the University of Ottawa, on long-term exposures of urban populations on reductions in life-expectancy.
- Drs. Zelikoff and Chen on cigarettes smoke and nanoparticles on birth defects.
- Drs. Reibman, Gordon and Klein on PM's effect on epigenetic control of IL-13.
- Nanoparticle research, with Dr. Gordon focused on in vitro responses; Dr. Xiong focused on physical and chemical characterization; and Dr. Chen focused on inhalation toxicology.
Susceptibility to Environmental Disease Focus Group
Terry Gordon and Richard Hayes, Co-leaders
Genetic and environmental factors are critical to disease susceptibility and the determinants of susceptibility are a central focus of the research of several toxicologists and epidemiologists in the NYU NIEHS Center. The Environment and Disease Susceptibility Focus Group is the forum for the development of interdisciplinary projects in disease susceptibility considering broadly the host susceptibility factors which render an individual more prone to environmentally-induced diseases and the mechanisms by which environmental agents make an individual more susceptible to disease. Members of the SFG are particularly interested in the role that age plays in the susceptibility to inhaled toxicants.
Several factors may be involved in the susceptibility of individuals or groups of individuals to environmental pollutants. These factors include age, gender, pre-existing disease, and genetics, each of which has been shown to play important roles in environmentally-related diseases such as cancer and asthma. The Susceptibility Focus Group utilizes epidemiology studies and animal models in identifying the contribution of these host factors to cardiopulmonary diseases and cancer. In addition, experimental designs are being developed that will permit the determination of the relative contribution of genetic and environmental factors to these adverse changes. Understanding the relative contributions of genes and environment is critical because the diseases associated with exposure to ambient pollutants appear to be as complex as the mix of pollutants encountered each day.
The Susceptibility Focus Group is led by Drs. Richard Hayes and Terry Gordon. Dr. Hayes, who joined the Department in February, 2009 from the NCI Intramural Program, has a primary research focus on cancer epidemiology, whereas Dr. Gordon's research interest is in inhalation toxicology, including the identification and understanding of the role of genetic host factors in the pathogenesis of pulmonary disease.
Highlights of Collaboration
- Drs. Zelikoff and Gordon rely on the services of the Inhalation Exposure Facility to conduct studies examining the mechanisms underlying the role of in utero exposure to cigarette smoke in adult onset disease. The increased sensitivity of early life stages is also being studied by Drs. Gordon (neonatal response to inhaled ozone) and Thurston (panel studies of the effects of air pollution on children with asthma and healthy children).
- Drs. Hayes, Ito, and Gordon have begun a collaboration to examine whether datasets developed in genome wide association studies can be utilized to test gene x environment interactions.
- The Experimental Animal Facility Core is used in Dr. Dai's collaborations with Drs. Rossman and Burns on the genetic susceptibility of cancer. They have explored the possibility of using knockout mouse models (PLK3 and BubR1-deficient mice) developed in Dr. Dai's laboratory and, as a result of the SFG discussions, these models will be tested by Drs. Gordon and Chen in their cigarette smoke and nanoparticle research.
- To better understand the pathogenesis of non-alcoholic fatty liver disease, atherosclerosis, and metabolic syndrome, Drs. LC Chen, Allina, and Odin collaborate to investigate interactions between the liver and cardiovascular disease susceptibility in PM inhalation animal studies.
- Drs. Zelikoff, Allina, Jackson, and Odin are collaborating to investigate the effect of in utero stress, such as exposure to cigarette exposure or nanoparticles, on liver disease progression in adult offspring in a mouse animal model. In particular, they are studying potential links between fetal gender and later life liver dysfunction.
- The role of genetic susceptibility in the response to inhaled pollutants has been examined by numerous investigators in the Center. Drs. LC Chen and Gordon have examined the contribution of host genetic factors to the adverse pulmonary effects of inhaled nanoparticles in several strains of inbred mice.
- NYU investigators have also examined the role of susceptibility factors in nanoparticle-induced aquatic toxicity. Drs. Wirgin and Gordon have used two environmentally relevant fish models to quantify inter-specific variation in susceptibility to the toxicity of a variety of nanoparticles including fullerenes and several metals. These studies have also compared the sensitivities of two different early life stages to nanoparticle toxicity under varying environmental conditions of salinities and natural organic material.
- Drs. Reibman, Shao, Liu, and others have been collaborating to examine various SNPs/haplotypes of candidate pathways for the susceptibility of asthma using the NYU/Bellevue Asthma Registry (founded by Dr. Reibman) which has about 1000 adult asthmatic patients and health controls. Gene-environment interactions with respect to environmental tobacco smoking and other exposures are being investigated in the context of asthma susceptibility studies using the admixed urban cohort.
- Dr. Grunig's laboratory is focused on lung immunology, and in a collaboration with Dr. Gordon, she is determining the role of IL-19 in regulating the response of immune cells in the lungs of mice that inhale a mixture of allergen and respirable PM from NYC.
- Drs. M Cohen and H Chen have begun a collaboration which examines the role of HIF-1α-related alterations in histone modification in the induction of pulmonary immunomodulation caused by metals that are commonly present in urban air pollution.
- Drs. Zelikoff and Steinetz have also examined the role of gender in response to toxic insult. They have demonstrated that adult female mice born to dams exposed to cigarette smoke during pregnancy are more sensitive than their male counterparts to asthma-like symptoms. In contrast, renatal exposure to cigarette smoke results in increased susceptibility of the male offspring to transplanted tumors.
- Dr. Zelikoff's fetal basis of adult disease studies in mice also investigate the effects of in utero exposure to cigarette smoke on later life cardiovascular changes related to dyslipidemia and on cigarette smoke-induced liver pathologies in the adult male and female offspring.
- Dr. Wirgin is the first to identify a mechanistic basis to resistance to toxicants in any vertebrate population. In collaboration with Dr. Hahn (Boston University Superfund Program), he has determined that Atlantic tomcod from the Hudson River PCBs Superfund site have developed a dramatic resistance to PCB toxicity due to a single genetic mutation (aryl hydrocarbon receptor 2). Resistance developed rapidly (50 generations) due to strong selective pressure.
- Drs. Zeleniuch-Jacquott and Wirgin collaborate on a study to assess whether polymorphisms in gene related to vitamin D metabolism and mode of action are related to breast cancer risk.