Peter Fuller, PhD
Prince Henry's Institute of Medical Research

Determinants of ligand dependent tissue specificity of the mineralocorticoid receptor

The mineralocorticoid receptor (MR) plays a central role in the pathophysiology of both hypertension and cardiac failure, yet an understanding of the molecular mechanisms lags behind that of other steroid receptors. The overall aim of this proposal is to identify components of MR signalling that differ between epithelial target tissues (kidney, colon) and cardiovascular tissues. Ligand and tissue-specificity of interaction has been well described for the other steroid receptors. These differences are based on several mechanisms, and this study will be the first to define the relative contributions of each of these mechanisms to MR-mediated signalling and form the basis of exploiting such differences for the development of novel, targeted therapeutic agents.

W. Lee Kraus, PhD
Cornell University

The Role of PARP-1 in Hormone-Regulated Transcription

The goal of these studies is to achieve a better understanding of the molecular mechanisms underlying chromatin-dependent regulation of estrogen receptor alpha (ERa) activity by poly(ADP-ribose) polymerase-1 (PARP-1), a multifunctional transcriptional coregulator and chromatin modulatory protein. Our broad hypothesis is that the coregulatory activity of PARP-1 at estrogen-regulated promoters is determined by (1) the local chromatin environment (e.g., chromatin composition, histone modifications) and (2) physical and functional interactions among PARP-1, ERa, other coregulators, and components of chromatin. In this proposal, we outline a series of experiments using a multidisciplinary approach with a complementary set of biochemical, cell-based, and genomic approaches that will test our broad hypothesis and will identify mechanisms of PARP-1 co-regulation of ERa and a subset of its target genes.