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

摘要 逼尿肌活动不足 (DU) 是由于膀胱肌肉力量不足而导致的排尿障碍，无法确保及时排尿。 和有效的膀胱排空。作为卷管理的一种障碍，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 肌肉障碍，DU 的一个关键特征是对膀胱容量失去敏感性。和DU一样，衰老也是 与体积灵敏度的损失有关。此外，老龄化的特点是失败的风险增加。 适应生物挑战，即恢复能力的丧失。因此我们认为 DU 不是逼尿肌疾病， 相反，它是衰老导致的膀胱感觉变化的非弹性端的表现。在这个 项目中，我们将研究“起搏器”离子通道在控制机制的年龄演化中的作用 对膀胱容量敏感性至关重要。我们假设 DU 与更严重的年龄有关 相关的变化。这些知识将使我们能够确定导致损失的控制因素 成功的、有弹性的老化和由此产生的无弹性表现为 DU。为了实现这些目标将 使用我们建立的小鼠膀胱测压模型来测试泌尿弹性并定义一个单独的 DU 组 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/细胞研究以及相关的组织水平实验，以实现我们的目标。由 利用康涅狄格大学老龄化中心内独特的综合专业知识， 神经科学部门和杰克逊现场实验室，我们将实现识别 DU 的目标 病理生理学并为改进的治疗模型做出贡献，该模型将 DU 视为一种适应性 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.