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.

下尿路症状 (LUTS)，特别是储存症状（尿失禁）是老年人的主要健康相关问题。然而，人们对衰老如何改变仍缺乏足够的了解正常的膀胱生理学，以及这些变化如何导致老年人 LUT 疾病的病因学。过去和现在的许多研究都集中在逼尿肌功能和中枢神经系统的变化上。衰老相关 LUT 功能的神经控制；然而，人们对它的作用知之甚少。这些事件中的尿路上皮（UT）。虽然尿路上皮以前被认为是一个简单的屏障，但它可以沟通通过局部尿路上皮传入信号通路与中枢神经系统相互作用。我们的初步数据显示，老年UT有改变线粒体功能，包括增加活性氧（ROS）的产生，我们假设导致溶酶体功能障碍、介质释放改变以及 UT 传入信号传导缺陷，最终导致尿动力学行为异常。因此，我们的总体假设是，与年龄相关的变化 UT 和邻近的膀胱壁会导致促衰老细胞表型，从而破坏 UT 细胞信号传导，从而导致老年人尿动力学行为异常。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串扰的影响墙。使用衰老（3-30 个月）大鼠模型，我们将在目标#1 中定义生物能学和氧化的变化通过使用功能测定测量线粒体功能的变化来影响尿路上皮衰老和建筑。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化和形态学工具来研究为什么降解和衰老的尿路上皮线粒体自噬受损。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 信号传导和由此产生的膀胱功能。我们将采用多学科方法包括发射器释放的测量和复杂的成像技术以及记录膀胱传入神经活动，以检查衰老和增加的线粒体氧化应激如何改变 UT- 细胞通讯。在每个目标中，我们还将检查是否可以减少治疗（mitotetempo；二甲双胍）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结合我们广泛的专业知识和资源，使我们的研究该团队处于独特的地位，可以研究直接和间接因素如何促进膀胱老化中的 UT 功能障碍。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative Stress Biomarkers in Age-Related Lower Urinary Tract Disorders: A Systematic Review.

年龄相关下尿路疾病的氧化应激生物标志物：系统评价。

DOI：
发表时间：
2022-03
期刊：
影响因子：
2.3
作者：
Khosla, Lakshay;Gong, Susan;Weiss, Jeffrey P;Birder, Lori A
通讯作者：
Birder, Lori A

Impact of Aging on Urinary Natriuretic Peptides in Nocturia and Nocturnal Polyuria.

衰老对夜尿症和夜间多尿症中尿钠肽的影响。

DOI：
发表时间：
2022-06
期刊：
影响因子：
2.3
作者：
Khosla, Lakshay;Boroda, Joseph U;Salama, Joshua;Rahman, Syed N;Gordon, Danielle J;Moy, Matthew W;Akivis, Yonatan;Akivis, Alla;Lazar, Jason M;Weiss, Jeffrey P;Birder, Lori A
通讯作者：
Birder, Lori A

Quantification of Aging-Related Decreases in Sensory Innervation of the Bladder Trigone in Rats.

大鼠膀胱三角区感觉神经支配与衰老相关的减少的量化。

DOI：
发表时间：
2024-02
期刊：
影响因子：
2.3
作者：
de Rijk, Mathijs M;Peter, Saša;Wolf;Heesakkers, John;van Koeveringe, Gommert A;Birder, Lori A
通讯作者：
Birder, Lori A

Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder.

膀胱电刺激后导水管周围灰质的神经元激活。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Meriaux, Céline;Hohnen, Ramona;Schipper, Sandra;Zare, Aryo;Jahanshahi, Ali;Birder, Lori A;Temel, Yasin;van Koeveringe, Gommert A
通讯作者：
van Koeveringe, Gommert A

Commentary on "Cognitive Function and Urologic Medications for Lower Urinary Tract Symptoms".

“下尿路症状的认知功能和泌尿科药物”评论。