Androgenic Regulation of Autophagy in the Prostate

描述（由申请人提供）：雄激素调节前列腺的生理发育和前列腺疾病的病理。尽管这些已知的雄激素作用，目前还不清楚哪些特定的细胞过程控制这些生物学，以及这些过程如何影响细胞的能量需求。从申请人现有的K01奖产生的初步结果表明，雄激素调节前列腺上皮细胞中的自噬。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。候选人的长期目标是开发新的治疗方法，用于治疗内分泌调节疾病，如良性前列腺增生（BPH）。本提案的主要目标是使用代谢组学和分子及细胞生物学的组合来定义雄激素介导的自噬在前列腺上皮细胞中的特定作用。中心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。这一假设是根据所产生的初步数据和其他小组发表的支持数据提出的。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，以及（B）生成为候选人新建立的独立研究计划奠定基础所需的数据。为了实现这些目标并检验假设，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识别的燃料源。在这个目标中，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。最初的研究表明，自噬导致细胞内脂肪库的破坏，这一过程可能产生氧化底物。在这第二个目标中，基于细胞的体外测定将与新兴的代谢组学技术结合使用，以机械地了解AR调节的细胞自噬如何影响生长和存活。这些研究将确定在存在或不存在功能性自噬的情况下用雄激素处理的前列腺细胞的代谢谱。完成这些目标将有助于申请人确定一个利基，这将有助于开发一个可资助的独立研究项目，解决AR生物学的一个重要但未充分探索的方面。 公共卫生相关性：拟议的项目与公共卫生有关，因为预计本研究中确定的机制可能会产生新的预防和治疗前列腺疾病的方法，如良性前列腺增生和癌症。先前的研究已经证明了脂肪代谢增加和自噬在前列腺肿瘤中的作用，因此，这些过程可能代表新的治疗靶点。此外，这些新信息将从根本上推进类固醇信号传导和前列腺生物学领域。

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.