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。尽管有这些已知的雄激素作用，但尚不清楚哪些特定的细胞过程控制着这些生物学，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代谢，这一发现对于理解前列腺稳态和疾病都具有重要意义。该候选人的长期目标是开发新的治疗方法来治疗内分泌调节疾病，如良性前列腺增生（BPH）。本研究的主要目标是结合代谢组学、分子和细胞生物学来确定雄激素介导的前列腺上皮细胞自噬的具体作用。主要假设是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表的支持数据的基础上制定的。本申请中描述的研究旨在(a)快速推进我们对雄激素受体（AR）细胞生物学的理解，(b)生成必要的数据，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验证假设，提出了两个具体目标。在Aim 1中，自噬的作用将在雄激素调节的细胞过程中确定。初步研究表明，雄激素促进前列腺上皮细胞的自噬通量，这一过程可能导致细胞利用以前未被识别的燃料来源。在这个目标中，分子和细胞生物学方法的融合将用于进一步描述AR对自噬的调节，并了解雄激素介导的自噬如何影响细胞生长和存活。在Aim 2中，将阐明ar调节的自噬在前列腺上皮细胞中的代谢后果。据推测，雄激素介导的自噬通过提供细胞额外的能量来源来影响细胞过程。最初的研究表明，自噬导致细胞内脂肪储存库的分解，这一过程可能产生氧化底物。在第二个目标中，体外细胞检测将与新兴的代谢组学技术结合使用，以机制地了解ar调节的细胞自噬如何影响生长和存活。这些研究将确定在功能性自噬存在或不存在的情况下，雄激素处理前列腺细胞的代谢谱。这些目标的完成将有助于申请人确定一个利基，这将促进一个可资助的独立研究项目的发展，该项目将解决AR生物学的一个重要但未被充分探索的方面。

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. PUBLIC HEALTH RELEVANCE: The proposed project is relevant to public health because it is anticipated that mechanisms identified in this study will likely yield new preventative and therapeutic approaches for prostatic diseases such as benign prostatic hyperplasia and cancer. Previous studies have demonstrated roles for increased fat metabolism and autophagy in prostatic neoplasias and as such, these processes may represent novel therapeutic targets. In addition, this new information will fundamentally advance the fields of steroid signaling and prostate biology.