AND ABSTRACT The androgen receptor (AR) is the master transcription factor responsible for development and maintenance of the male sex phenotype. Aberrant AR activity is associated with multiple disorders, including but not limited to metastatic prostate cancer, androgenetic alopecia, and Kennedy's disease. Cell-based studies have reported AR is regulated through numerous processes, including 1) androgen stimulation; 2) anti-androgen inhibition; 3) intramolecular contacts among its domains; 4) association with various protein coactivators and corepressors. Despite its importance in disease etiology, the mechanistic details underlying AR regulation are largely unknown due to historical difficulty isolating pure, active multidomain AR variants. This research will employ biochemical and complementary structural methods ? including electron and atomic force microscopy, and x-ray crystallography ? to illuminate the molecular determinants of AR activation through identification of surfaces important for intramolecular and cofactor-mediated stimulation (Aim 1), and for AR inhibition by anti-androgen binding and self-regulatory modes of autoinhibition (Aim 3). The molecular details revealed by the biochemical and structural studies will be validated in biologically relevant AR-dependent cell lines to determine the functional outcomes of these interactions on cell morphology, growth, AR signaling and the AR cistrome (Aim 2). The findings from these studies will provide novel insight for modes of dimerization, intramolecular regulation, and DNA binding for AR as well as other type I nuclear hormone receptors, including the progesterone, glucocorticoid, and mineralocorticoid receptors, and can facilitate potential design of novel AR-targeting drugs. This research is in line with the goals of the NIGMS of generating fundamental knowledge that will bear implication for human disease and health. The comprehensive training plan described will enable the investigator to achieve her career goals of running an independent academic laboratory dedicated to studying fundamental modes of AR transcriptional regulation in the context of its active, hyperactivated, and inhibited states, and will provide biochemical, structural, and functional insight to the consequences of its aberrant activity in disease. As a joint mentee in top prostate cancer and structural biology laboratories at Memorial Sloan Kettering Cancer Center and the Rockefeller University, she will receive diverse training in prostate biology and electron microscopy that will expand the investigator's biological understanding and technical repertoire that will enable significant innovation in her future research. The leadership, networking, and communication skills she will acquire through the MOSAIC UE5 will facilitate her transition to independence, and equip her to enhance diversity in the scientific workforce.
The androgen receptor is a type I nuclear hormone receptor and master transcription factor responsible for differentiation and development of the male phenotype. Its hyperactivation is associated with multiple diseases, including metastatic prostate cancer, androgenetic alopecia, androgen insensitivity syndrome, and Kennedy?s disease. This proposal seeks to understand the mechanism of androgen receptor regulation and determinants of its aberrant activity using biochemical, structural, and cellular methods, which can facilitate the development of novel androgen receptor inhibitors and lend mechanistic insight towards other related nuclear hormone receptors.
