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Bladder Mucosal Dysfunction During Aging

衰老过程中的膀胱粘膜功能障碍

基本信息

批准号：
9540177
负责人：
Gerard L Apodaca
金额：
$ 60.63万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9540177
关键词：
Adverse effects Affect Age Aging Anatomy Animals Architecture Autophagocytosis Behavior Biochemical Bioenergetics Biogenesis Biological Assay Bladder Bladder Control Bladder Diseases Bladder Dysfunction Bladder mucosa Calcium Cathepsins B Cell Aging Cell Communication Cell surface Cells Complex Coupled Cytoplasm Data Defect Development Diagnosis Disease Drug Targeting Elderly Esthesia Etiology Event Exocytosis Fibrosis Foundations Functional disorder Genus Hippocampus Health Health Care Costs Homeostasis Hydrolase Image Imaging Techniques Impairment Incontinence Institutionalization Interdisciplinary Study Lead Lower urinary tract Lysosomes Measurement Measures Mechanics Mediator of activation protein Metabolic Pathway Metformin Mitochondria Modality Modeling Molecular Morphology Muscle function Nervous system structure Neurologic Organ Organelles Oxidative Stress Pathway interactions Peptide Hydrolases Phenotype Physiology Population Positioning Attribute Process Production Quality of life Quantitative Reverse Transcriptase PCR Rattus Reactive Oxygen Species Research Resources Role Signal Pathway Signal Transduction Societies Stimulus Stress Sum Symptoms Urinary Incontinence Urodynamics Urothelium Western Blotting afferent nerve age effect age related aged anti aging cost detrusor muscle improved in vivo insight interdisciplinary approach lower urinary tract symptoms mitochondrial dysfunction protein degradation receptor sensory input tool transcription factor

项目摘要

Lower urinary tract symptoms (LUTS), in particular storage symptoms (urinary incontinence) are a major health related problem in the elderly. Yet, there remains insufficient understanding of how aging alters normal bladder physiology, and how these changes contribute to the etiology of LUT disorders in the elderly. Much of research past and present, has focused on detrusor muscle function and changes in the central neurological control of aging-related LUT function; however, much less is known about the role of the urothelium (UT) in these events. While previously thought of as a simple barrier, the urothelium communicates with the CNS via a local urothelial-afferent signaling pathway. Our preliminary data show that aged UT has altered mitochondrial function, including increased production of reactive oxygen species (ROS), which we hypothesize leads to lysosomal dysfunction, altered release of mediators, and defects in UT-afferent signaling, culminating in abnormal urodynamic behavior. Thus, our overall hypothesis is that age-related changes in the UT and adjacent bladder wall result in a pro-aging cellular phenotype that disrupts UT-cell signaling resulting in abnormal urodynamic behavior in the elderly. Our multidisciplinary research team will elucidate the effect of aging and oxidative/lysosomal stress on urothelial physiology and the impact this has on cross talk between the UT and other cells within the bladder wall. Using an aging (3-30 mo) rat model, we will in Aim #1 define how changes in bioenergetics and oxidative stress impact urothelial aging by using functional assays to measure changes in both mitochondrial function and architecture. In Aim #2, we will determine how lysosomal dysfunction contributes to urothelial aging. Here we will use stereology as well as biochemical and morphological tools to examine why degradation and mitophagy are impaired in aging urothelium. In Aim #3, we will determine if increasing mitochondrial/lysosomal function will enhance UT-signaling and resultant bladder function. We will use a multi-disciplinary approach including measurement of transmitter release and sophisticated imaging techniques coupled with recording bladder afferent nerve activity to examine how aging and increased mitochondrial oxidative stress alters UT- cell communication. In each aim, we will also examine whether treatments (mitotempo; metformin) that reduce oxidative stress/lysosome dysfunction can improve urothelial (and in vivo bladder function) in aged rats. In sum, our intriguing preliminary data combined with our extensive expertise and resources places our research team in a unique position to examine how direct and indirect factors promote UT dysfunction in bladder aging.

下尿路症状（LUTS），特别是储存症状（尿失禁）是一种