Androgenic Regulation of Autophagy in the Prostate

描述(申请人提供)：雄激素调节前列腺的生理发育和前列腺疾病的病理。尽管有这些已知的促雄激素作用，但目前还不清楚是哪些特定的细胞过程管理着这些生物，以及这些过程究竟如何影响细胞的能量需求。申请人现有的K01奖产生的初步结果表明，雄激素调节前列腺上皮细胞的自噬。此外，这种调节影响整体细胞新陈代谢，这一发现对于理解前列腺内稳态和疾病都具有重要意义。候选人的长期目标是开发治疗内分泌调节疾病的新方法，如良性前列腺增生症(BPH)。这项建议的主要目标是结合代谢组学和分子细胞生物学来确定雄激素介导的自噬在前列腺上皮细胞中的特殊作用(S)。这是一个中心假设，雄激素通过调节自噬和随后的脂肪酸氧化，促进细胞生长和存活。这一假设是在生成的初步数据和其他小组发布的支持数据的基础上提出的。本申请中描述的研究旨在(A)迅速提高我们对雄激素受体(AR)细胞生物学的理解，并(B)产生必要的数据，为候选人新建立的独立研究计划奠定基础。为了实现这些目标并检验假设，本文提出了两个具体目标。在目标1中，将确定自噬在雄激素调节的细胞过程中的作用。初步研究表明，雄激素促进了前列腺上皮细胞的自噬流量，这一过程可能导致细胞利用以前未知的燃料来源。在这一目标中，分子和细胞生物学方法的融合将被用来进一步描述AR对自噬的调节，并了解雄激素介导的自噬如何影响细胞的生长和存活。在目标2中，AR调节的自噬的代谢后果将在前列腺上皮细胞中阐明。假设雄激素介导的自噬通过为细胞提供额外的能量来源来影响细胞过程(S)。最初的研究表明，自噬导致细胞内脂肪储存库的崩溃，这一过程可能会产生氧化的底物。在第二个目标中，体外基于细胞的分析将与新兴的代谢组技术结合使用，以机械地了解AR调节的细胞自噬如何影响生长和生存。这些研究将确定在存在或不存在功能性自噬的情况下，雄激素处理的前列腺细胞的代谢情况。这些拟议目标的完成将帮助申请者确定一个利基，这将促进一个可资助的独立研究计划的发展，该计划解决AR生物学一个重要但未被探索的方面。

DESCRIPTION (provided by applicant): Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. Despite these known androgenic roles, it is unclear which specific cellular processes govern these biologys and exactly how these processes impact cellular energy demands. Preliminary results generated from the applicant's existing K01 award demonstrate that androgens regulate autophagy in prostate epithelial cells. Further, this regulation impacts overall cell metabolism, a finding that is of significance for understanding both prostatic homeostasis and disease. The long-term goal of the candidate is to develop new therapeutic approaches for the treatment of endocrine-regulated diseases such as benign prostatic hyperplasia (BPH). The primary goal of this proposal is to use a combination of metabolomics and molecular and cellular biology to define the specific role(s) of androgen-mediated autophagy in prostate epithelial cells. It is the central hypothesis that androgens, through the regulation of autophagy and subsequent fatty acid oxidation, promote cellular growth and survival. This hypothesis has been formulated on the basis of the generated preliminary data and supporting data published by other groups. The studies described in this application are designed to (a) rapidly progress our understanding of androgen receptor (AR) cellular biology and (b) generate the data necessary to build the foundation for the candidate's newly established independent research program. To accomplish these goals and test the hypothesis, two specific aims are proposed. In Aim 1 the role of autophagy will be determined in androgen-regulated cellular processes. Preliminary studies suggest that androgens promote autophagic flux in prostate epithelial cells, a process that may result in the cellular utilization of previously unrecognized fuel sources. In this aim a fusion of molecular and cellular biology approaches will be used to both further delineate AR's regulation of autophagy and understand how androgen-mediated autophagy affects cellular growth and survival. In Aim 2, the metabolic consequences of AR-regulated autophagy will be elucidated in prostate epithelial cells. It is hypothesized that androgen-mediated autophagy impacts cellular processes by providing cells an additional energy source(s). Initial studies indicate that autophagy leads to the breakdown of intracellular fat reservoirs, a process that could produce substrates for ¿-oxidation. In this second aim, in vitro cell-based assays will be used in conjunction with emerging metabolomic technologies to mechanistically understand how AR-regulated cellular autophagy influences growth and survival. These studies will define the metabolic profile of prostate cells treated with androgens in the presence or absence of functional autophagy. Completion of these proposed aims will help the applicant define a niche that will facilitate the development of a fundable independent research program that addresses an important, but underexplored aspect of AR biology.