Bladder Mucosal Dysfunction During Aging

衰老过程中的膀胱粘膜功能障碍

• 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
• 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

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(LUT)，特别是储尿症状(尿失禁)是一种 与老年人健康相关的主要问题。然而，对于老龄化是如何改变的，人们仍然理解不足。 正常的膀胱生理，以及这些变化如何在老年人LUT疾病的病因中起作用。 过去和现在的许多研究都集中在逼尿肌的功能和中央的变化。 衰老相关的LUT功能的神经控制；然而，人们对其作用知之甚少 尿路上皮(UT)在这些事件中。尽管以前被认为是一种简单的屏障，但尿路上皮 通过局部尿路上皮-传入信号通路与中枢神经系统联系。我们的初步数据显示，年龄较大的德克萨斯大学 线粒体功能改变，包括活性氧簇(ROS)的产生增加，我们 假设导致溶酶体功能障碍，介质释放改变，UT传入信号缺陷， 最终导致异常的尿动力学行为。因此，我们的总体假设是年龄相关的变化 UT和邻近膀胱壁导致促衰老的细胞表型，扰乱UT细胞信号转导，导致 老年人尿流动力学行为异常。 我们的多学科研究团队将阐明衰老和氧化/溶酶体应激对 尿路上皮生理学及其对UT和膀胱内其他细胞之间的串扰的影响 墙。使用衰老(3-30个月)的大鼠模型，我们将在目标1中定义生物能量学和氧化的变化。 应激对尿路上皮衰老的影响--通过功能测定来衡量两种线粒体功能的变化 和建筑。在目标2中，我们将确定溶酶体功能障碍如何导致尿路上皮老化。这里 我们将使用体视学以及生物化学和形态学工具来研究为什么退化和 在老化的尿路上皮，丝裂原吞噬功能受损。在目标3中，我们将确定是否增加线粒体/溶酶体 功能将增强UT信号和由此产生的膀胱功能。我们将采用多学科的方法 包括发射机释放的测量和与记录相结合的复杂成像技术 膀胱传入神经活动检查衰老和线粒体氧化应激增加如何改变UT 蜂窝通讯。在每个目标中，我们还将检查治疗(MitoTEMPO；二甲双胍)是否会减少 氧化应激/溶酶体功能障碍可改善老年大鼠的尿路上皮(和体内膀胱功能)。在……里面 总之，我们耐人寻味的初步数据与我们广泛的专业知识和资源相结合，使我们的研究 小组在一个独特的位置，研究直接和间接因素如何促进膀胱老化中的UT功能障碍。