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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的衰老是许多给公众健康带来负担的常见疾病的最大单一危险因素。这尤其是在前列腺中确实如此。前列腺是男性性附属腺，对生殖很重要。然而，作为男性随着年龄的增长，前列腺会经历典型的衰老变化，即纤维化。前列腺纤维化的老化原因泌尿系统症状几乎每个人只要活得足够长，都会遭受这种症状。我们的团队致力于定义老化的前列腺及其与整体健康相关的泌尿系统症状。迄今为止的老化机制尚未针对非恶性前列腺进行彻底测试或靶向。相反雄激素调节途径和α肾上腺素能活性主导了该领域。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老化和纤维化，最终导致前列腺功能障碍、泌尿系统症状和整体不佳健康。线粒体功能障碍已成为公认的衰老机制。然而，角色前列腺线粒体功能障碍尚未得到彻底测试。部分原因是因为几乎没有人们了解线粒体在前列腺功能中的作用，但尚未找到模型来测试它。到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 4 个目标。目标1将使用线粒体复合物 I 的化学抑制剂评估前列腺线粒体功能障碍的增益电子传递链并确定前列腺老化是否加速，最终导致功能失调前列腺。目标 2 将确定线粒体功能障碍导致衰老的分子机制纤维化。目标 3 确定特定细胞和解剖区域中线粒体功能障碍的定位男性前列腺，包括种族差异以及小鼠下尿路的差异。目标 4 测试促线粒体健康药物在逆转线粒体功能障碍、前列腺衰老和人类和小鼠衰老模型中的泌尿功能障碍。确定与药理学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非常重要达到延长健康寿命的目标。这种方法的潜在转化影响很大，因为拟议的 senolytics 已获得 FDA 批准，可以迅速纳入临床试验。于完成这项工作，我们将更好地了解线粒体功能障碍在前列腺衰老中的作用以及如何针对这一途径来改善泌尿系统和整体健康。此外，新的老化模型将为未来的衰老和泌尿科相关研究而开发和更好地表征。