Excellence in Research: Developmental regulation of WDR77 coordinates prostate growth and differentiation during the development through puberty

Clark Atlanta University, Atlanta GA

Investigators

Abstract

This research will address how altered male hormone levels during development through puberty affect growth and differentiation of the prostate gland. The project will first determine whether male hormone at lower levels (during puberty) leads to growth of the prostate gland and, in contrast, if higher levels of the male hormone (post-puberty) promote the prostate’s differentiation. The research will then investigate how the male hormone’s action is switched during prostate development throughout puberty. The proposed research represents a novel study concept that relates to the basic biology of prostate development. The various age-related diseases in older adult prostate reflect the loss of developmental coordination of cell proliferation and differentiation. Therefore, the research may also help to understand the development of various prostatic diseases in older men. The project will also directly support graduate and undergraduate student training and promote scientific research in a minority population at this HBCU. The mammalian prostate gland passes through several phases of rapid growth and differentiation during development. The molecular mechanisms that determine growth and differentiation stages, as well as coordinating these two processes are less defined. This research will address these critical questions. The goal of the project is to study molecular events and mechanisms that coordinate cell growth and differentiation during prostate development from adolescent (proliferating) to young adult (quiescent/differentiated) stage. The research will first investigate the androgen function in a dosage-dependent manner to control growth and differentiation of the prostate during mouse development through puberty. A concentration threshold at which the androgen action is switched from growth promotion to growth inhibition/differentiation will be determined. Previous studies have identified the WDR77 protein localized in the cytoplasm at the early (during puberty, proliferating) stage of the prostate development drives cell proliferation. In adult (post-puberty, quiescent/differentiated) prostate, the protein in the nucleus functions as an androgen receptor cofactor to promote cell differentiation. The research will then investigate whether WDR77 mediates the androgen’s role to coordinate growth and differentiation during the prostate development. How change of androgen levels alters epigenetic modifications, leading to altered expression of AR-target genes as well as WDR77 subcellular localization will be studied using chromatin immunoprecipitation and gene promoter mapping. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.