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

本研究将探讨男性激素水平在青春期发育过程中如何影响前列腺的生长和分化。该项目将首先确定较低水平的男性激素（青春期）是否会导致前列腺的生长，相反，较高水平的男性激素（青春期后）是否会促进前列腺的分化。这项研究将调查在整个青春期前列腺发育过程中，雄性激素的作用是如何改变的。提出的研究代表了一个新的研究概念，涉及前列腺发育的基本生物学。老年前列腺的各种年龄相关疾病反映了细胞增殖和分化发育协调性的丧失。因此，这项研究也可能有助于了解老年男性各种前列腺疾病的发展。该项目还将直接支持研究生和本科生的培养，并促进该HBCU少数民族的科学研究。哺乳动物的前列腺在发育过程中要经历几个快速生长和分化的阶段。决定生长和分化阶段以及协调这两个过程的分子机制尚未明确。这项研究将解决这些关键问题。该项目的目标是研究从青春期（增殖）到年轻成人（静止/分化）阶段前列腺发育过程中协调细胞生长和分化的分子事件和机制。该研究将首先研究雄激素在小鼠发育至青春期期间以剂量依赖的方式控制前列腺生长和分化的功能。将确定雄激素作用从促进生长转变为抑制生长/分化的浓度阈值。先前的研究发现，定位于前列腺发育早期（青春期、增生期）细胞质中的WDR77蛋白驱动细胞增殖。在成人（青春期后，静止/分化）前列腺中，细胞核中的蛋白质作为雄激素受体辅助因子促进细胞分化。接下来，该研究将调查WDR77是否介导雄激素在前列腺发育过程中协调生长和分化的作用。雄激素水平的变化如何改变表观遗传修饰，导致ar靶基因表达的改变以及WDR77亚细胞定位将通过染色质免疫沉淀和基因启动子定位进行研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.