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

卓越研究：WDR77 的发育调节可协调青春期发育期间的前列腺生长和分化

• 批准号: 2300390
• 负责人: Zhengxin Wang
• 金额: $ 91.4万
• 依托单位: Clark Atlanta University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2300390&HistoricalAwards=false
• 关键词: Excellence; Research; Developmental; regulation; WDR77

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.

这项研究将解决如何改变男性激素水平在发展过程中，通过青春期影响前列腺的生长和分化。 该项目将首先确定较低水平的雄性激素（青春期）是否会导致前列腺的生长，相反，较高水平的雄性激素（青春期后）是否会促进前列腺的分化。 然后，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转换的。 拟议的研究代表了一种新的研究概念，涉及前列腺发育的基础生物学。 老年人前列腺的各种年龄相关疾病反映了细胞增殖和分化的发育协调性丧失。 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训，并促进在该HBCU的少数人群中进行科学研究。哺乳动物前列腺在发育过程中经历了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还不太清楚。 这项研究将解决这些关键问题。 该项目的目标是研究从青少年（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。 该研究将首先以剂量依赖性方式研究雄激素功能，以控制小鼠发育至青春期期间前列腺的生长和分化。 将确定雄激素作用从生长促进转换为生长抑制/分化的浓度阈值。 先前的研究已经确定，在前列腺发育的早期（青春期，增殖期），位于细胞质中的WDR 77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因子发挥作用，以促进细胞分化。 然后，该研究将研究WDR 77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WDR 77的亚细胞定位将使用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NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。