Effect of Aging on Urothelial Function

衰老对尿路上皮功能的影响

• 批准号: 9144989
• 负责人: Gerard L Apodaca
• 金额: $ 68.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144989
• 关键词: Adverse effects; Affect; Aging; Aging-Related Process; Apical; Biological Assay; Biopsy; Bladder; Bladder Control; Bladder Urothelium; Blood Vessels; Blood flow; Cell Aging; Cell Communication; Cells; Collaborations; Communication; Complex; Computer Simulation; Data; Development; Diagnosis; Disease; Elderly; Electric Capacitance; Elements; Epidemiologic Studies; Esthesia; Etiology; European; Event; Exhibits; Extracellular Matrix; Failure; Foundations; Functional Imaging; Functional disorder; Goals; Head; Health; Health Personnel; Human; Incidence; Incontinence; Indium; Information Technology; Injury; Institutionalization; Interdisciplinary Study; Label; Letters; Link; Lower urinary tract; Maps; Measurement; Measures; Mediator of activation protein; Modality; Modeling; Molecular; Morphology; Mucous Membrane; Muscle function; Natural regeneration; Nerve; Nervous system structure; Neurologic; Ohio; Optics; Overactive Bladder; Perfusion; Peripheral Nervous System; Permeability; Physiological; Physiology; Positioning Attribute; Process; Quality of life; Rattus; Research; Research Training; Resistance; Resources; Role; Sensory; Signal Pathway; Signal Transduction; Smooth Muscle; Societies; Structure; Sum; Surface; Symptoms; Techniques; Tissues; Universities; Urea; Urinary Incontinence; Urine; Urothelial Cell; Urothelium; Viral; Water; Western Blotting; afferent nerve; age effect; age related; design; detrusor muscle; lower urinary tract symptoms; mathematical model; patient registry; regenerative; research study; response to injury; sensory input; sensory mechanism; stressor

 DESCRIPTION (provided by applicant): Lower urinary tract symptoms (LUTS), in particular storage symptoms (urinary incontinence) are a major health related problem in the elderly. LUTS remain largely under diagnosed and poorly managed by healthcare providers and incontinence has been cited as the major reason for institutionalization of the elderly. There is little information to explain 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 in these events. While previously known of as a simple barrier, the urothelium is associated with the nervous system and sensory input arising at the apical surface of the umbrella cell layer regulates bladder function to the CNS via a local urothelial-afferent signaling pathway. Changes in sensory mechanisms are important in older persons diagnosed with overactive bladder or incontinence. The goals of this project are to explore the effect of aging and age-related processes (such as changes in blood flow) on urothelial-related functional elements in the bladder wall. Our preliminary data show that aging correlates with altered urothelial expression of mediators, decreased vascular perfusion and inability to regenerate the urothelium after injury, all of which can adversely impact sensation and bladder function. Thus, our overall hypothesis is that aging involves altered urothelial-afferent signaling that can result in symptoms of bladder overactivity and failure to store urine leading to incontinence or underactivity and retention in the elderly. Our multidisciplinary research team will elucidate the effect of aging o urothelial remodeling in the bladder and cross talk between bladder wall layers and sensory function. We will have unprecedented access to human information (patient registries, bladder biopsies, functional imaging) that will aid us in designing and interpreting the observations as well as stimulating translational application of this research, using an aging (3- 30 mo) rat model. In Aim #1, we will characterize mechanisms by which aging (and changes in blood flow) affects urothelial cell barrier functions by measuring transepithelial resistance and permeability. We will also assess vascular perfusion and explore the involvement of trophic factors on barrier functions. Aim #2 will characterize mechanisms underlying aging changes in urothelial sensory functions using functional assays and molecular techniques. Finally, Aim #3 will characterize mechanisms by which aging affects communication in the bladder wall. We will examine mechanisms underlying these changes by use of afferent nerve recording including use of viral-constructs to label afferents and optical mapping techniques to examine cell-cell interactions in the bladder wall. In sum, our intriguing preliminary data, combined with our extensive expertise and resources (including mathematical and computer modeling), places our research team in a unique position to examine mechanisms that may be responsible for underlying symptoms (overactivity; inability to empty) involved in the aging bladder.

 描述(申请人提供)：下尿路症状(LUT)，特别是储尿症状(尿失禁)是老年人的主要健康问题。LUT在很大程度上仍然得不到医疗保健提供者的诊断和管理不善，大小便失禁被认为是老年人住院的主要原因。几乎没有信息来解释衰老如何改变正常的膀胱生理，以及这些变化如何导致老年人LUT障碍的病因。过去和现在的大部分研究都集中在逼尿肌功能和衰老相关LUT功能的中枢神经控制的变化；然而，对尿路上皮在这些事件中的作用知之甚少。尽管以前被认为是一种简单的屏障，但尿路上皮与神经系统有关，伞状细胞层顶端的感觉输入通过局部尿路上皮-传入信号通路调节膀胱功能到中枢神经系统。感觉机制的改变对于被诊断为膀胱过度活动或大小便失禁的老年人很重要。该项目的目标是探索衰老和与年龄相关的过程(如血流变化)对膀胱壁中与尿路上皮相关的功能元件的影响。我们的初步数据显示，衰老与介质的尿路上皮表达改变、血管灌注量减少以及损伤后尿路上皮不能再生有关，所有这些都会对感觉和膀胱功能产生不利影响。因此，我们的总体假设是，衰老涉及尿路上皮传入信号的改变，这可能会导致症状。 在老年人中，膀胱过度活动和不能储存尿液导致大小便失禁或活动不足和滞留。我们的多学科研究团队将阐明衰老对膀胱尿路上皮重塑的影响，以及膀胱壁各层与感觉功能之间的相互作用。我们将史无前例地获得人类信息(患者登记、膀胱活检、功能成像)，这些信息将帮助我们设计和解释观察结果，并利用衰老(3-30个月)的大鼠模型刺激这项研究的翻译应用。在目标1中，我们将通过测量跨上皮阻力和通透性来表征衰老(和血流的变化)影响尿路上皮细胞屏障功能的机制。 我们还将评估血管灌流，并探讨营养因子对屏障功能的影响。目的#2将利用功能分析和分子技术表征尿路上皮感觉功能衰老变化的潜在机制。最后，目标3将描述衰老影响膀胱壁交流的机制。我们将通过使用传入神经记录来研究这些变化背后的机制，包括使用病毒构建体标记传入细胞，以及使用光学映射技术来检查膀胱壁中细胞与细胞的相互作用。总而言之，我们耐人寻味的初步数据，再加上我们广泛的专业知识和资源(包括数学和计算机建模)，使我们的研究团队处于独特的地位，可以检查可能导致膀胱老化的潜在症状(过度活动；无法排空)的机制。