BAGCHI, Milan

 Department of Molecular and Integrative Physiology

Ph.D. (1984) University of Nebraska (Lincoln)

  Research Topics

     - Gene Regulation by steroid and thyroid hormones

     - Coactivators/Corepressors

     - Gene Networks

   Research Interests

  The research in my laboratory explores the mechanisms of gene regulation by steroid and thyroid hormones. Whereas the steroid hormones estrogen and progesterone are principal regulators of development and function of female reproductive tissues such as ovary, uterus, and mammary gland, the thyroid hormone exerts profound influence on growth and differentiation of a wide variety of tissues, especially during early development. The cellular actions of these hormones are mediated through specific high affinity nuclear receptor proteins, which function as ligand-inducible transcription factors. The hormone-receptor complexes interact with the hormone-responsive genes in the target cells and regulate RNA synthesis. The overall goal of my laboratory is to gain a clear understanding of the molecular pathways that translate the signals initiated by hormone binding to nuclear receptors into modulation of the expression of specific cellular genes.

   Recent studies revealed the existence of novel cellular cofactors designated coactivators and corepressors, which modulate the gene regulatory activities of nuclear hormone receptors in target tissues. A coactivator interacts with the hormone-bound nuclear receptor and functions as a critical positive modulator of receptor-dependent gene activation. A corepressor, on the other hand, interacts with certain unliganded nuclear receptors to promote receptor-mediated transcriptional repression. The coactivator and corepressor proteins exist in multiprotein complexes, which may function by regulating chromatin structure and transcription initiation at the target promoter in an opposing fashion. To explore the mechanisms of gene regulation by steroid and thyroid hormone receptors, we employ in vitro reconstituted systems in which a recombinant steroid or thyroid hormone receptor regulates transcription of a target reporter gene in cell-free nuclear extracts. We are currently exploiting these hormone-regulated gene expression systems to dissect the functional roles of the coactivator and corepressor proteins in receptor-mediated transcriptional activation and repression, respectively. We expect that such knowledge will open up new avenues to control the tissue-specific action of nuclear hormone receptors in a variety of human disease states such as breast cancer, endometriosis, and resistance to thyroid hormone.

  Another goal of the laboratory is to identify the gene networks that are targeted for regulation by a steroid hormone in a hormone responsive tissue. Using a new technology, termed cDNA microarray, we have now identified a spectrum of genes that are regulated by the steroids, progesterone and estrogen, in the female reproductive tract. We have now started to examine the expression profile and hormonal regulation of a number of these newly isolated genes in the reproductive tissues under various physiological conditions. For selected genes, we have embarked on an analysis of their function during reproduction by employing gene knockout animal models.

  Key Words   DNA microships and rea-time PCR Creation of transgenic animals, Purification

   Current Research Funding   NIH, NIDDK, NICHD Gustavus and Louise Pfeiffer Research Foundation, New York State Department of Health

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