It has been determined that the overall conformation of nuclear receptors is influenced by the nature of the ligand to which they bind and that the resulting differences in conformation enable the differential recruitment of cofactors. Despite these accepted concepts, it still remains to be determined (a) which receptor surfaces are responsible for each biological activity and (b) how these surfaces function mechanistically. I have identified one such surface, a unique stretch of proline residues located towards the N-terminus of AR, that is necessary for maximal AR-mediated growth and the regulation of select androgen target genes. The long-term goal of the candidate is to develop novel therapeutic approaches for endocrine maladies. The primary goal of this proposal is to use a combination of bioinformatics and molecular biology to define the specific role(s) of the AR polyproline domain and two identified proteins that interact with this specific surface. These goals will be achieved using the superb research environment at Duke University Medical Center within both the Department of Pharmacology and Cancer Biology and the Duke Institute of Genome Sciences and Policy. To accomplish these goals the following specific aims are proposed:
Aim 1 : Determine the role of the polyproline domain within AR in androgen-regulated biological processes.
Aim 2 : Identify and validate the specific signaling pathways elicited by AR and its polyproline domain that drive cellular effects such as growth, migration, and actin reorganization.
Aim 3 : Evaluate the impact of genetic modification of the AR polyproline domain and its cofactors, SH3YL1 and Lyn kinase, on the activity of selective androgen receptor modulators (SARMs). This work will provide a definitive assessment of the role of the polyproline domain in AR biology and advance our basic understanding of AR signaling. Insights from this work will facilitate mechanism-based screens for the development of compounds, SARMs, with useful tissue-selective activities.
It is anticipated this project will contribute to the knowledge base needed to develop pharmacological strategies that can selectively modulate androgen-regulated actions. At the conclusion of these studies we will be able to directly link a specific biological process to a particular AR-cofactor interaction. This new information will be invaluable for the future design of AR ligands.
