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

摘要 老年科学方法治疗泌尿症状需要了解 正常确保膀胱控制动态平衡/异位平衡，以及它们如何受到衰老的影响 这些在很大程度上仍未被发现。我的一般假设是，老化的膀胱表型 是否表示实现自适应控制所需的多方面机制的衰退性 关于大脑对膀胱内容物的“了解”程度。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，我将在我的实验室学习和建立发现 神经与我们的R01资助的关于HCN离子通道在 肾上腺素能逼尿肌松弛及衰老对这一过程的影响。因为我们有 假设HCN是神经内分泌(交感)和旁分泌(粘膜)的媒介 对逼尿肌活动的影响，我们还将确定衰老对粘膜和 HCN在逼尿肌反应性随年龄增长的异质性中的作用 我们的体内和体外研究。除了这项实验室工作，我还将提供临床和 在膀胱控制生理学方面的实验室专业知识是我们最近成立的多学科 一组专家老龄化研究人员。 除了更细致入微地了解神经内分泌对膀胱的影响 体积传感，该奖项下开发的实验室工具将为新项目做出贡献 重点研究逼尿肌活动的旁分泌/粘膜决定因素，以及脊髓/脑干 过程，因为这些容量感知控制机制提供了对急性(膀胱)的弹性 和慢性(衰老)挑战来控制生理。这些相同的工具也将促进 我们对膀胱表型在老年人常见的尿路功能障碍中的作用进行了研究- 相关疾病，如阿尔茨海默病和其他神经退行性疾病。这个 我们合作小组开发的翻译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稳态负荷的影响 危害无症状、适合社会的膀胱控制，尽管急性和慢性 与老龄化相关的挑战。 实验室技术培训和老化研究被纳入项目计划。 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， 让我朝着致力于老化膀胱研究的事业目标前进。

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.