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Center for Research on Environmental DiseaseJohn Digiovanni, Ph.D. Project DescriptionThe primary objective of the Center for Research on Environmental Disease (CRED) is to study the mechanisms by which environmental factors may cause or influence human disease and to develop methods for early detection, prevention, and control of environmentally-related diseases. The unifying theme for the CRED is to define host responses to environmental exposures and to understand how diet, genetic and epigenetic factors influence these responses. The investigators vision is to make a significant contribution to human health in the environmentally-related diseases cancer, obesity, diabetes, cardiovascular disease and asthma. The problems of environmental health are complex, requiring an understanding of the sources of chemical and physical stresses in the environment, their modes of transport and transformation, the routes of human exposure, the mechanisms through which the agents exert their effects, and the possible ways their actions may be influenced by modifiers or co-factors, including diet and genetic background. The successful study of these complex problems requires multidisciplinary and interdisciplinary approaches. To tackle this vast array of problems, the CRED brings together, in an integrated effort, a multidisciplinary group of established scientists with a broad range of expertise. Research within the CRED take place in four major Research Focus Areas: i) Environmental and Molecular Epidemiology; ii) Mechanisms of Environmental Carcinogenesis; iii) Diet, Energy Balance and Environmental Disease Risk; and iv) Genetics and Epigenetics of Early Life Exposure. Three important underlying scientific themes cut across these Research Focus Areas and provide the impetus for collaboration between members in different Focus Areas: analysis of the biological responses to defined environmental exposures; effects of diet and diet-gene interactions on environmental disease risk; and mechanisms by which early life environmental exposures affect environmental disease risk in the adult. The research efforts of Center members in all Research Focus Areas is enhanced by access to the following five Facility Cores: 1) Molecular Biology; 2) Analytical Instrumentation; 3) Histology and Tissue Processing; 4) Cell and Tissue Analysis; 5) Integrated Health Sciences (IHS). In addition, an Administrative Core provides strategic planning, formalizes collaborative interactions, provides for enrichment activities, provides oversight for the Facility Cores, and administers the Pilot Project Program; an Environmental Health Research Career Development Program provides cross training and mentoring support for junior Faculty, contributing to the development of the next generation of environmental health scientists; and a Community Outreach and Education Core translates and disseminates important research findings of the Center to the general public and to policymakers in response to community needs. The new Integrated Health Sciences Facility Core represents the keystone of the investigator’s efforts to enhance collaborations between basic and clinical researchers in order to bring bench-level findings to bear on real world environmental exposure problems. Program HighlightsGene-Environment Interactions and Cancer RiskRecent studies have demonstrated that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor suppressor gene defect in the adult. Utilizing rats carrying a germline defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene predisposed to uterine leiomyomas, CRED researchers showed that an early life exposure to diethylstilbestrol (DES) during development of the uterus increased tumor suppressor gene penetrance from 65% to >90% as well as tumor multiplicity and size in genetically predisposed animals, but failed to induce tumors in wild-type rats. Results from these studies suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor suppressor gene penetrance in genetically susceptible individuals. Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A; 102 (24):8644-9; 2005.
PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15937110) M.D. Anderson News Release NIEHS News Release Ultraviolet B Exposure and Non-Melanoma Skin CancerIn studies to elucidate the role that UVB-induced mutagen sensitivity may play in susceptibility to non-melanoma skin cancer (NMSC) and cutaneous malignant melanoma (CMM), CRED members initiated a novel case-control study to assess the frequency of UVB-induced chromatid breaks per cell in skin cancer patients versus the control group. Researchers found that UVB-induced chromosome breaks were higher in NMSC patients than in the control group, but were the same in CMM patients and the control group. These results indicate that only non-melanoma skin cancers are strongly associated with exposure to UVB radiation, while UVA radiation may be responsible for DNA damage in melanocytes giving rise to melanoma. Wang LE, Xiong P, Strom S, Goldberg LH, Lee JE, Ross MI, Mansfield PF, Gershenwalk JE, Prieto VG, Cormier JN, Duvic M, Clayman GL, Weber RS, Lippman SM, Amos CI, Spitz MR, Wei Q. In vitro sensitivity to ultraviolet B light and skin cancer risk: A case-control analysis. J Natl Cancer Inst. 97:1822-1831; 2005.
PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16368944) M.D. Anderson News Release Molecular "Brake" to Cell DeathCytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. In this seminal study CRED researchers discovered that physiological levels of nucleotides, were shown to inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1. In various apoptotic systems caspase activation is preceded or accompanied by decreases in overall intracellular NTP pools. Microinjection of nucleotides inhibits whereas experimentally reducing NTP pools enhances both CC and apoptotic stimuli-induced cell death. These results suggest that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome, the nucleotide barrier, to undergo apoptosis cell death. Chandra, D., Bratton, S. B., Person, M. D., Tian, Y., Martin, A. G., Ayres, M., Fearnhead, H. O., Gandhi, V., Tang, D. G. Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome. Cell 125 (7): 1333-46: June 2006 M.D. Anderson News Release |
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