Detrusor Underactivity as an HCN-mediated Failure of Resilience in Aging

摘要 逼尿肌活动不足（DU）是由于膀胱肌肉努力不足而导致的排尿障碍，以确保及时排尿。 和有效的膀胱排空。作为一种容量管理障碍，DU通常与 尿失禁和其他泌尿系统症状，尤其是在晚年。尽管这个词暗示着膀胱 肌肉紊乱，DU的一个关键特征是对膀胱容量的敏感性丧失。与DU一样，衰老也是 与体积敏感性丧失有关。此外，衰老的特点是失败的风险增加， 适应生物挑战，即丧失复原力。因此，我们认为DU不是逼尿肌疾病， 相反，它是衰老的膀胱感觉变化谱的非弹性端的表现。在这 本计画将探讨“起搏器”离子通道在控制机制年龄演化中的角色 对膀胱容量敏感性至关重要。我们假设DU与更严重的年龄相关- 相关的变化。这一知识将使我们能够确定造成损失的控制因素， 成功的，有弹性的老龄化和由此产生的非弹性表现为DU。为了实现这些目标， 使用我们建立的小鼠膀胱测压模型来测试尿弹性，并将DU组与 年龄组我们的研究方法将包括单细胞基因组测序，电生理学， 分子/细胞研究和相关的组织水平实验，以解决我们的目标。通过 利用康州大学老龄化中心独特的综合专业知识， 神经科学部门，和现场杰克逊实验室，我们将解决的目标，确定杜 病理生理学，并有助于改善治疗模型，认识到DU作为一种适应性 失败

ABSTRACT Detrusor Underactivity (DU) is a voiding impairment due to insufficient bladder muscle effort to ensure timely and efficient bladder emptying. As a disorder of volume management, DU is often associated with incontinence and other urinary symptoms, especially in later life. Despite the term suggesting a bladder muscle disorder, a key characteristic of DU is loss of sensitivity to bladder volume. Like DU, aging is also associated with loss of volume sensitivity. Moreover, aging is characterized by increasing risk of failure to adapt to biologic challenge, i.e. loss of resilience. We therefore propose that DU is not a detrusor disease, rather it is a manifestation of the nonresilient end of the spectrum of bladder sensory changes of aging. In this project we will investigate the role of a “pacemaker” ion channel in the age evolution of a control mechanism critical to bladder volume sensitivity. We hypothesize that DU is associated with the more severe age- associated changes. This knowledge will allow us to determine the control factors contributing to the loss of successful, resilient aging and the resulting non-resilience manifested as DU. To accomplish these goals will use our established mouse cystometry model to test urinary resilience and define a DU group separate from age groups. Our research methods will include single cell genomic sequencing, electrophysiology, molecular/cellular investigations, and correlative tissue-level experiments in order to address our objective. By taking advantage of the uniquely available combined expertise within the UConn Center on Aging, Neurosciences department, and on-site Jackson laboratory, we will address the goal of identifying DU pathophysiology and contributing to an improved therapeutic model which recognizes DU as an adaptive failure.