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：
10371207
负责人：
Gerard L Apodaca
金额：
$ 59.63万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371207
关键词：
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 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 Stress Sum Symptoms Urinary Incontinence Urodynamics Urothelial Cell 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 mechanical stimulus mitochondrial dysfunction protein degradation receptor sensory input side effect 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.

较低的尿路症状（LUTS），特别是储存症状（尿失禁）是老年人的主要健康问题。然而，人们对衰老的变化如何保持不足正常的膀胱生理以及这些变化如何导致老年人的LUT疾病的病因。过去和现在的大部分研究都集中在迫切肌肉功能和中央的变化上与衰老相关的LUT功能的神经控制；但是，关于这些事件中的尿铺上皮（UT）。虽然以前被认为是一个简单的障碍，但尿路上皮沟通与中枢神经系统通过局部尿路上的信号通路。我们的初步数据表明，老化的UT有线粒体功能的改变，包括增加活性氧（ROS）的产生，我们假设导致溶酶体功能障碍，介体的释放改变以及UT-fargement信号传导的缺陷，达到异常尿动力行为。因此，我们的总体假设是与年龄相关的变化 UT和相邻的膀胱壁会导致促成的细胞表型，该表型破坏了UT细胞信号传导，导致老年人的尿动力学异常。我们的多学科研究团队将阐明衰老和氧化/溶酶体压力对尿路上皮生理及其对膀胱内UT和其他细胞之间的串扰的影响墙。使用老化（3-30 mo）大鼠模型，我们将在AIM＃1中定义生物能和氧化的变化如何变化压力通过使用功能分析来测量两个线粒体功能的变化来影响尿路上皮老化和建筑。在AIM＃2中，我们将确定溶酶体功能障碍如何促进尿路上皮衰老。这里我们将使用立体学以及生化和形态学工具来研究为什么退化和线粒体在衰老的尿路上皮中受到损害。在AIM＃3中，我们将确定线粒体/溶酶体是否增加功能将增强UT信号和最终的膀胱功能。我们将使用多学科的方法包括测量发射机释放和复杂成像技术与记录膀胱传入神经活性以检查衰老和增加线粒体氧化应激如何改变UT- 细胞通信。在每个目标中，我们还将检查降低的治疗方法（Mitotempo;二甲双胍）是否会减少氧化应激/溶酶体功能障碍可以改善老年大鼠的尿路上皮（和体内膀胱功能）。在总而言之，我们有趣的初步数据与我们的广泛专业知识和资源相结合团队处于独特的位置，可以检查直接和间接因素如何促进膀胱衰老中的UT功能障碍。