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

摘要 逼尿肌活动不足(DU)是一种由于膀胱肌肉力量不足而导致的排尿损害，以确保及时 和高效的膀胱排空。作为一种卷管理的障碍，DU经常与 大小便失禁和其他尿路症状，尤其是在晚年。尽管这个词让人联想到膀胱 肌肉紊乱，DU的一个关键特征是对膀胱容量失去敏感性。和DU一样，老龄化也是 与体积敏感度的丧失有关。此外，老龄化的特点是不能 适应生物挑战，即丧失韧性。因此，我们认为DU不是逼尿肌疾病， 相反，这是衰老引起的膀胱感觉变化频谱中无弹性的一端的一种表现。在这 我们将研究“起搏器”离子通道在控制机制的年龄进化中的作用。 对膀胱容量敏感度至关重要。我们假设DU与更严重的年龄有关- 关联的更改。这一知识将使我们能够确定造成损失的控制因素 成功的、有弹性的老化和由此产生的无弹性表现为DU。要实现这些目标，将 使用我们建立的小鼠膀胱测压模型来测试尿弹性，并定义一个独立于 各年龄段。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。通过 利用康涅狄格州大学老龄中心独一无二的综合专业知识， 神经科学部和现场杰克逊实验室，我们将解决确定DU的目标 病理生理学，并有助于改进的治疗模式，承认DU为适应性 失败了。

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.