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: 10346265
• 负责人: WILLIAM A RICKE
• 金额: $ 60.27万
• 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/10346265
• 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; Ultrasonography; 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/antagonist; 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; 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.

抽象的 衰老是许多常见疾病的最大危险因素，这些疾病负担了公共卫生的负担。尤其是 在前列腺中为真。前列腺是男性性配饰，对生殖很重要。但是，如 男性年龄的前列腺经历了典型的衰老变化，纤维化。老化的纤维化前列腺原因 尿症状，如果每个人的寿命足够长，几乎都会困扰着每个人。我们的团队领导了 定义老化的前列腺及其在整体健康中的相关尿症状。迄今为止的老化机制 尚未彻底测试或针对非恶性前列腺。而不是调节雄激素 途径和α肾上腺素能活性占主导地位。该应用程序的长期目标是 更好地了解线粒体功能障碍以及相关的分子和细胞机制如何促进 前列腺衰老和纤维化，最终导致前列腺功能障碍，尿症状和整体差 健康。线粒体功能障碍已成为公认的衰老机制。但是， 前列腺中的线粒体功能障碍尚未进行彻底测试。部分是因为几乎没有 了解线粒体在前列腺功能中的作用，并且尚未确定任何模型来测试它。到 更好地了解线粒体功能障碍在衰老前列腺中的作用，我们将执行4个目标。目标1意志 评估使用线粒体复合物I的化学抑制剂I的前列腺线粒体功能障碍的增益 电子传输链，并确定前列腺衰老是否加速最终导致功能失调 前列腺。 AIM 2将确定线粒体功能障碍诱导衰老和 纤维化。 AIM 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，包括种族的差异以及小鼠的下尿路。 AIM 4测试 促核苷脂药物在逆转线粒体功能障碍，前列腺衰老和 衰老的人和小鼠模型中的尿功能障碍。识别与药理年龄相关的 对新型前列腺老化动物模型的干预措施改善线粒体稳态将是高度的 希望延长健康范围的目标。这种方法的潜在翻译影响很高， 由于拟议的塞溶剂已经获得了FDA的批准，并且可以迅速纳入临床试验中。在 完成这项工作，我们将更好地了解线粒体功能障碍在衰老前列腺中的作用 以及如何针对这一途径以改善尿和整体健康。此外，新的衰老模型将是 开发和更好地为未来的衰老和泌尿科研究。