Elucidating hallmarks of aging in the development of lower urinary tract dysfunction (LUTD)

阐明下尿路功能障碍 (LUTD) 发展中的衰老特征

• 批准号: 10494151
• 负责人: WILLIAM A RICKE
• 金额: $ 58.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494151
• 关键词: 2 year old; 3-Dimensional; Address; Adrenergic Agents; Adult; Age; Aging; Anatomy; Androgens; Animal Model; Animals; Area; Automobile Driving; Benign Prostatic Hypertrophy; Biogenesis; Biological Assay; Biology; Cell Aging; Cells; Chemicals; Clinical Trials; Collagen; Complex; Computer software; Data; Development; Disease; Electron Transport; Event; Extracellular Matrix; FDA approved; Fibrinogen; Fibroblasts; Fibrosis; Fracture; Functional disorder; Future; Genetic; Genetic Induction; Genus Hippocampus; Gland; Goals; Health; Histologic; Histopathology; Homeostasis; Human; Hyperplasia; Hypertrophy; Image; In Vitro; Increased frequency of micturition; Inflammation; Intervention; Lower urinary tract; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Methods; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Molecular; Mus; Mutation; Nodule; Non-Malignant; Octogenarian; Outcome Measure; Oxygen Consumption; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Predisposition; Process; Production; Prostate; Prostatic; Prostatic hypertrophy; Public Health; Quality of life; Race; Reactive Oxygen Species; Reproduction; Research; Respiration; Risk Factors; Role; Specimen; Stromal Cells; Symptoms; Testing; Tissues; Treatment Cost; Urethra; Work; age related; aged; animal data; burden of illness; chemical genetics; clinically relevant; comorbidity; effectiveness testing; experience; experimental study; fall risk; functional disability; healthspan; human model; improved; in vivo; inhibitor; lower urinary tract symptoms; male; man; men; mitochondrial dysfunction; mortality; mouse model; normal aging; novel; patient derived xenograft model; preclinical study; reconstruction; reproductive; restoration; sex; side effect; spectrograph; therapeutic development; translational impact; translational potential; ultrasound; urinary; urologic

ABSTRACT Aging is the single largest risk factor for many common diseases that burden public health. This is especially true in the prostate. The prostate is a male sex accessory gland that is important in reproduction. However, as men age the prostate undergoes a prototypical aging change, fibrosis. The aged fibrotic prostate causes urinary symptoms which will afflict nearly every man if they live long enough. Our team has led an effort to define the aged prostate and its associated urinary symptoms in overall health. To date aging mechanisms have not been thoroughly tested or targeted for the nonmalignant prostate. Rather androgen regulated pathways and alpha adrenergic activity have dominated the field. The long-term goal of this application is to better understand how mitochondrial dysfunction and related molecular and cellular mechanisms promote prostate aging and fibrosis, ultimately leading to prostate dysfunction, urinary symptoms and overall poor health. Mitochondrial dysfunction has become an accepted mechanism of aging. However, the role of mitochondrial dysfunction in the prostate has not been thoroughly tested. In part this is because there is little understanding of the role of mitochondria in prostate function and no models have been identified to test it. To better understand the role of mitochondrial dysfunction in the aging prostate, we will perform 4 Aims. Aim 1 will assess the gain of prostatic mitochondrial dysfunction using chemical inhibitors of mitochondrial complex I of the electron transport chain and determine if prostatic aging is accelerated ultimately leading to a dysfunctional prostate. Aim 2 will determine the molecular mechanism by which mitochondrial dysfunction induces aging and fibrosis. Aim 3 identifies the localization of mitochondrial dysfunction in specific cells and anatomical areas of the prostate of men, including differences in race as well as in the lower urinary tract of mice. Aim 4 tests the effectiveness of pro-mitochondrial health drugs in reversing mitochondrial dysfunction, prostate aging, and urinary dysfunction in human and mouse models of aging. Identifying pharmacological age related interventions in novel prostate aging animal models to improve mitochondrial homeostasis would be highly desirable towards the goal of prolonging healthspan. The potential translational impact of this approach is high, as the proposed senolytics are already FDA approved and can be rapidly included into clinical trials. Upon the completion of this work, we will better understand the role of mitochondrial dysfunction in the aging prostate and how to target this pathway for better urinary and overall health. Furthermore new aging models will be developed and better characterized for future aging and urological related research.

摘要 老龄化是许多常见疾病的最大风险因素，这些疾病给公共卫生造成了负担。这是特别的 这在前列腺癌是正确的。前列腺是男性的附腺，在生殖过程中很重要。然而，由于 男性随着年龄的增长，前列腺会经历一种典型的衰老变化，即纤维化。老年前列腺纤维性变的病因 如果活得足够长，几乎每个人都会出现尿路症状。我们的团队领导了一项努力 在整体健康中定义老年前列腺及其相关的尿路症状。到目前为止的老化机制 没有对非恶性前列腺癌进行彻底的测试或靶向。而是受雄激素调控 通路和阿尔法肾上腺素能活动主导了这一领域。此应用程序的长期目标是 更好地了解线粒体功能障碍和相关的分子和细胞机制是如何促进 前列腺老化和纤维化，最终导致前列腺功能障碍、尿路症状和整体欠佳 健康。线粒体功能障碍已成为公认的衰老机制。然而，它的作用是 前列腺中的线粒体功能障碍还没有得到彻底的测试。这在一定程度上是因为 了解线粒体在前列腺功能中的作用，目前还没有确定测试它的模型。至 为了更好地了解线粒体功能障碍在前列腺老化中的作用，我们将执行四个目标。目标1将 使用线粒体复合体I的化学抑制剂评估前列腺线粒体功能障碍的进展 电子传递链并确定是否加速了前列腺老化，最终导致功能障碍 前列腺。目的2将确定线粒体功能障碍导致衰老和 纤维化症。目的3确定线粒体功能障碍在特定细胞和解剖区域的定位 男性的前列腺，包括种族差异以及小鼠下尿路的差异。AIM 4测试 促线粒体保健药物在逆转线粒体功能障碍、前列腺老化和 人类和小鼠衰老模型中的排尿功能障碍。识别与药理年龄相关的 对新型前列腺衰老动物模型进行干预以改善线粒体稳态将是非常重要的 对于延长健康寿命的目标是可取的。这种方法的潜在翻译影响很高， 由于建议的抗衰老药物已获得FDA批准，并可迅速纳入临床试验。在此之前 完成这项工作，我们将更好地了解线粒体功能障碍在前列腺老化中的作用 以及如何针对这一途径，以更好地促进尿路和整体健康。此外，新的老龄化模式将是 为未来的老龄化和泌尿学相关研究开发和更好地描述特征。