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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：
10684318
负责人：
WILLIAM A RICKE
金额：
$ 58.47万
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/10684318
关键词：
2 year old 3-Dimensional Acceleration 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 Myofibroblast Nodule Non-Malignant Octogenarian Outcome Measure Oxygen Consumption Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Predisposition Process Production Proliferating 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 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 pharmacologic preclinical study prototype 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.

摘要