Examining the role of defective oxidative phosphorylation in the normal and diseased prostate

摘要 下尿路症状（LUTS）是老年男性的一个重大负担，通常是良性的结果。 前列腺增生（BPH）。虽然BPH/LUTS在适当的医疗干预下通常不会致命， 导致许多男性随着年龄的增长生活质量显著下降。此外，BPH/LUTS增加风险 死亡率和每年数十亿美元的医疗费用。目前有一个BPH/LUTS的子集 FDA批准的治疗（α受体阻滞剂，5ARI）失败的患者，这些患者已被证明有 前列腺纤维化增加。目前还没有FDA批准的针对纤维化或衰老过程的药物， BPH/LUTS，即使老化是最大的风险因素。这一建议旨在更好地了解 衰老、纤维化和线粒体功能障碍在BPH/LUTS中的作用。线粒体功能障碍是一种 这是衰老和纤维化的标志，尚未就BPH/LUTS进行彻底研究。初步 数据表明氧化磷酸化（OXPHOS）是一种线粒体途径， BPH/LUTS功能障碍。本提案的目标1旨在调查OXPHOS与 破坏和下尿路功能障碍（LUTD）在一种新的小鼠模型。本提案的目标2将 研究OXPHOS破坏与纤维化相关途径之间的联系，使用遗传学方法， 功能丧失细胞系模型。最后，目标3将致力于确定一种新的治疗途径， 油酸作为线粒体代谢调节剂。总的来说，这些目标将改善我们的整体 了解BPH/LUTS的潜在过程，特别关注衰老，线粒体功能障碍， 和纤维化。该提案希望提供转化成果，最终可以改善患者护理， 治疗方案。

ABSTRACT Lower urinary tract symptoms (LUTS) are a significant burden to aging men and are often as a result of benign prostatic hyperplasia (BPH). While BPH/LUTS is not commonly fatal with proper medical intervention, it does cause a significant reduction in quality of life for many men as they age. Furthermore, BPH/LUTS increases risk of mortality and results in billions of dollars in healthcare costs annually. There is currently a subset of BPH/LUTS patients that fail FDA-approved treatments (α-blockers, 5ARI), and these patients have been shown to have increased prostatic fibrosis. There is no FDA-approved medication targeting fibrosis or the aging process in BPH/LUTS, even though aging is the greatest risk factor. This proposal aims to develop a better understanding about the role of aging, fibrosis, and mitochondrial dysfunction in BPH/LUTS. Mitochondrial dysfunction is a hallmark of both aging and fibrosis and has not been thoroughly studied in relation to BPH/LUTS. Preliminary data suggests that oxidative phosphorylation (OXPHOS) is a mitochondrial pathway contributing to cellular dysfunction in BPH/LUTS. Aim 1 of this proposal intends to investigate the connection between OXPHOS disruption and lower urinary tract dysfunction (LUTD) in a novel mouse model. Aim 2 of this proposal will investigate the connection between OXPHOS disruption and pathways associated with fibrosis, using genetic loss-of-function cell line models. Finally, Aim 3 will work to identify a new pathway of interest for treatment, using oleic acid as a mitochondrial metabolism modulator. Collectively, these aims will improve our overall understanding of the processes underlying BPH/LUTS, with a special focus on aging, mitochondrial dysfunction, and fibrosis. This proposal hopes to provide translational outcomes that can eventually improve patient care and treatment options.