Urinary Symptoms and Incontinence in Aging Reflect Loss of Lower Urinary Tract Resilience

摘要 老年科学方法泌尿系统症状需要了解的机制， 通常确保膀胱控制稳态/变应性以及它们如何受到衰老的影响，但 这些大部分仍未被发现。我的一般假设是老化的膀胱表型 是实现适应性控制所需的多方面机制衰退的表现 大脑对膀胱内容物的“了解”。发现这些适应机制 和系统，以及它们如何受到老化的影响，将解决这一关键的知识差距。 在这个项目中，我将学习和建立在我的实验室需要发现的技术， 神经相关的R 01资助的研究HCN离子通道的作用， 肾上腺素能逼尿肌松弛和衰老对这一过程的影响。既然我们有 假设HCN作为神经内分泌（交感神经）和旁分泌（粘膜）的介质 影响逼尿肌活动，我们还将确定老化对粘膜和 HCN对年龄增加的逼尿肌反应性异质性的贡献 我们的体内和体外研究。除了这项实验室工作，我将提供临床和 膀胱控制生理学的实验室专业知识，我们最近成立的多学科 一群衰老研究专家。 除了对神经内分泌对膀胱的影响有更详细的了解外， 体积感测，在此奖项下开发的实验室工具将有助于新的项目 着重于逼尿肌活动的旁分泌/粘膜决定因素，以及脊髓/脑干 由于这些容量感测控制机制提供了对急性（膀胱）疾病的恢复力， 填充）和慢性（老化）挑战以控制生理学。这些工具还将促进 我们对膀胱表型在老年人常见的泌尿功能障碍中的作用的研究- 相关疾病，如阿尔茨海默病和其他神经退行性疾病。的 我们合作小组开发的转化研究工具将支持旨在 更好地理解衰老和认知储备丧失作为非稳态负荷的影响， 损害无症状的、社会上适当的膀胱控制， 与衰老相关的挑战。 实验室技术和老化研究方面的培训已纳入项目计划。 这种培训与研究目标相结合，将使我能够实现特定的里程碑， 推动我朝着我的事业目标，致力于老化膀胱研究。

ABSTRACT A geroscience approach to urinary symptoms requires knowledge about the mechanisms that normally ensure bladder control homeostasis/allostasis and how they are impacted by aging, yet these remain largely undiscovered. My general hypothesis is that the aging bladder phenotype is the expression of decline of multifaceted mechanisms needed to achieve adaptive control over what the brain “knows” about bladder content. Discovering these adaptive mechanisms and systems, and how they are impacted by aging, will address this critical knowledge gap. In this project, I will learn and establish the technologies in my laboratory needed to discover the neural correlates to our R01-funded investigations on the role of the HCN ion channel in adrenergic detrusor relaxation and the impact of aging on this process. Since we have hypothesized HCN as a mediator of neuroendocrine (sympathetic) and paracrine (mucosal) influences over detrusor activity, we will also determine the impact of aging on mucosal and HCN contributions to the age-increased heterogeneity of detrusor responsiveness observed in our in-vivo and in-vitro studies. Alongside this laboratory work, I will provide clinical and laboratory expertise with bladder control physiology to our recently formed multidisciplinary group of expert aging researchers. In addition to a more granular understanding of the neuroendocrine influence over bladder volume sensing, the laboratory tools developed under this Award will contribute to new projects focusing on the paracrine/mucosal determinants of detrusor activity, and spinal/brainstem processes, as these mechanisms of volume sensing control provide resilience to acute (bladder filling) and chronic (aging) challenges to control physiology. These same tools will also facilitate our investigations of the role of a bladder phenotype in urinary dysfunctions common in age- associated disease such as Alzheimer’s disease and other neurodegenerative conditions. The translational research tools developed in our collaborative group will support new projects aimed at greater understanding of the impact of aging and loss of cognitive reserve as allostatic loads compromising asymptomatic, socially appropriate bladder control despite the acute and chronic challenges associated with aging. Training in laboratory techniques and aging research are incorporated into the project plan. This training in combination with the research goals will allow me to achieve specific milestones, moving me towards my goal of career dedication to aging bladder research.