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Research Overview
Nuclear Receptors and
Disease
Dr. Welsh’s lab investigates the role of
nuclear receptors in normal development, aging and cancer. Nuclear
receptors are intracellular proteins that sense and respond to small,
lipid-soluble compounds (ligands) including hormones,
nutrients, xenobiotics and phytochemicals.
Many of these ligands are present in the environment,
thus nuclear receptors represent one mechanism for cells to respond to
environmental changes. Once activated by their ligands,
nuclear receptors participate in complex networks to regulate the expression of
target genes that control normal development, cell proliferation and survival,
tissue metabolism, drug disposition and homeostasis. Nuclear receptors are
known to influence the aging process, and deregulation of these networks has
been linked to common diseases such as cancer, diabetes and obesity. Because of
their critical roles in normal development, aging and disease processes,
nuclear receptors represent attractive targets for drug discovery. Examples of
nuclear receptor interacting compounds currently in clinical use include drugs
for hormone replacement and breast cancer, anti-diabetic drugs,
cholesterol-lowering drugs and anti-inflammatory agents.
The overall goals of the Welsh lab’s
experiments are to provide insight into the molecular mechanisms by which
nuclear receptors work, and to clarify their role in specific tissues and
disease processes. Our emphasis is on nuclear receptor ligands
derived from diet (vitamin D, retinoids, fatty acids) and from the environment (phytochemicals,
xenobiotics, oxysterols). We believe that more detailed understanding
of the molecular mechanisms of nuclear receptor action will lead to more
rationale drug design and more appropriate dietary recommendations for
prevention of chronic diseases.
Major areas of research:
- Nuclear receptor regulatory networks in
differentiation, development,
metabolism and aging
- Nutrition and prevention of breast, prostate and
colon cancer
- Stem cell renewal and lineage determination in
the bone marrow mesenchymal compartment
- Genomic patterns of nuclear receptor action
Current projects:
- Characterizing cancer risk in genetic models of
vitamin D deficiency
- Analyzing the role of nuclear receptors in
cellular responses to environmental stress, inflammation and DNA damaging
agents
- Defining the roles of nuclear receptors (VDR,
PPAR, RXR) in stem cell renewal and differentiation of bone marrow mesenchymal stem cells
- Studying interactions between adipocytes and epithelial cells in mammary gland
Last updated on 02/18/2009
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