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Four Research Cores have been developed to provide for collaborative interactions and expansion of investigator-initiated research programs through the exchange of scientific information and use of new technologies:
EHS Center Research Cores: Gene Regulation and Genetics Research Core Core Leader: Melissa A. Runge-Morris, M.D. The development and progression of metabolic and hormone-responsive disease in humans is orchestrated by a complex merger of both genetic and environmental factors. Individuals at risk may have inherent genetic polymorphisms that, when coupled with an induced capacity for in situ xenobiotic metabolism, amplifies their chances for disease development. Environmental agents such as polychlorinated aromatic hydrocarbons (e.g. dioxins, polychorinated biphenyls), organochlorine pesticides (e.g. DDTs, chlordecone), and dietary heterocyclic amines (e.g. PhIP), acting as either xeno-hormones, mutagens or false cell signaling molecules, have been implicated to disrupt and re-direct gene expression. Through the years, the concept of environmental disease has shifted away from that of high-dose toxic chemical exposures. Researchers in a health-conscious modern society are now challenged with the specter that low-dose, chronic exposure to a variety of common environmental agents may play a pivotal role in the pathogenesis and progression of common diseases such as diabetes, heart disease and cancer. The overall mission of the Gene Regulation and Genetics Research Core is to achieve a greater understanding of the role of environmental factors in the genesis and progression of human metabolic and hormone-responsive diseases. This mission is in direct alignment with that of the EHS Center which is to unravel the molecular and cellular underpinnings of human disease mechanisms by fostering state-of-the art, hypothesis-driven research in environmental health science. In order to accomplish its mission, the members of the Gene Regulation and Genetics Research Core have formed two key focus or "research interest" groups that are dedicated to the promotion and establishment of interdisciplinary environmental health research programs. The two main focus groups of the Gene Regulation and Genetics Research Core are: The two main focus groups of the Gene Regulation and Genetics Research Core are:
A third focus group, the Developmental and Reproductive Risk Focus Group, is in the planning stages. Members of this emerging focus group are dedicated understanding the impact of the environment on gene expression programs during development. Gene Regulation and Genetics Research Core members meet on the third Monday of each month from 3:00 to 4:00 PM at the Institute of Environmental Health Sciences, Wayne State University. In order to create strong collaborations in environmental health sciences that apply state-of-the-art EHS Center resources to mechanism-based research in gene regulation, the Gene Regulation and Genetics Research Core has adopted the following 5-point strategy:
Scientists who are interested in learning more about Gene Regulation and Genetics Research Core activities should contact the Core Leader, Dr. Melissa Runge-Morris at m.runge-morris@wayne.edu. Cell Signaling & Function Research Core Core Leader: John J. Reiners, Jr., Ph.D. Associate Core Leader: Raymond Mattingly, Ph.D.
The Cell Signaling and Function Research Core consists of 22 members with faculty appointments in the Wayne State University Institute of Environmental Health Sciences, Department of Biological Sciences, School of Pharmacy and School of Medicine. The overall mission of the Core is to encourage and facilitate the interaction and collaboration of Center scientists who have interests in understanding the mediators, modulators and mechanisms of signal transduction in normal, neoplastic and toxicant-perturbed cells and tissues, and to relate these signaling processes to cellular function or toxicity. Focal areas of common interest involve the study of the divergent effects of metals and problems involving cell cycle control and apoptosis. The broad-based goals of the Core are to:
For additional information contact Dr. John Reiners, john.reiners.jr@wayne.edu. Early Events and Environmental Factors in Proliferative Breast Disease and Cancer Core Leader: Fred Miller, Ph.D. Atypical hyperplasia and ductal carcinoma in situ are high risk breast lesions having an increased risk for breast cancer but it is not clear why some progress to cancer and others do not. The further progression of breast lesions from these early high risk states may be dependent upon subsequent exposure to environmental factors that might alter gene expression through gene regulation in the high risk breast epithelial cells or alter non-lesion host tissues such as the immune system, endocrine system, or tissue stromal interactions within the lesion. This research core facilitate interactions among a broad based core of scientists to examine the effects of environmental factors implicated in breast cancer using a unique panel of cells derived from a woman with fibrocystic disease. The panel includes immortal normal cells (MCF10A), premalignant cells that form high risk lesions when xenografted into nude mice (MCF10AT1 cells), and a variant that forms high grade ductal carcinoma in situ (MCF10DCIS.com). The cells are stem cells which are able to differentiate into both, a distinct myoepithelial cell rim, with prominent intact basement membrane around each ductular structure, and luminal epithelial cells. The MCF10DCIS.com induces the mouse stroma to change into cancer activated fibroblasts (myofibroblasts that produce stromal derived factor-1) and these lesions progress to invasive ductal carcinoma (IDC) within 8 weeks. Investigators in the core have expertise to examine the effect of environmental factors on 1) the progression of the premalignant xenografts to invasive ductal carcinoma by histopathology, 2) the proteome of the high risk lesions and stromal components from xenografts using 2-dimensional non-porous reverse phase HPLC, 3) the loss of specific genes and promoter hypermethylation of specific genes, 4) the dynamics of stromal interactions, 5) the early genomic abnormalities indicative of genomic instability, and 6) proteome function. An additional interest will be prevention of the environmental factor-mediated response using inhibitors of the proteasome and specific inhibitors of tumor-stromal interactions. For additional information contact Dr. Fred R. Miller at millerf@karmanos.org.Environmental Pediatrics Research Core Core Leader: Jeffrey W. Taub, M.D. The prenatal environment and exposures have been linked to the development of a variety of pediatric and adult diseases including cancer, cardiovascular disease, kidney disease and neuropsychological development. As a representative disease, the pediatric core has been studying the prenatal origin of childhood leukemia, the most common form of cancer in the pediatric population. Current projects include: I) Determining retrospectively the proportion of childhood acute lymphoblastic leukemia (ALL) cases which have a prenatal origin based on the detection of preleukemic/leukemic clones detected in blood spots of Guthrie newborn screening cards. Additional studies will determine whether there are differences in frequencies of prenatal origins of ALL between Caucasian and African American children, and whether prenatal exposures may account for the 2-3-fold higher frequency of ALL in Caucasian compared to African American children. II) Examining the relationship of prenatal pesticide exposure (quantified by meconium analysis) and the generation of preleukemic cells detected in umbilical cord blood samples. An additional focus of the core is the study of the pharmacogenomics of childhood leukemia and identifying genes associated with chemotherapy metabolism and response.As a representative group, Down syndrome children have an unique genetic susceptibility to develop acute leukemia and have a striking increased sensitivity to certain chemotherapy agents resulting in extremely high cure rates in cases of acute myeloid leukemia. Microarray technology is currently being used to identify genes associated with both leukemogenesis and treatment response in collaboration with Dr. Alan Dombkowski and the Microarray and Bioinformatics Facility Core of the EHS Center.
For additional information contact Dr. Jeffrey Taub at jtaub@med.wayne.edu.
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