Molecular mechanisms of mechanosensing in the urinary tract

项目摘要 下尿路（LUT）功能问题非常常见：在成人中 在40岁以上的人中，高达70%的受访者报告了LUT病理。这部分是因为 排尿的生理学（排尿）是复杂的：它需要膀胱中的平滑肌， 尿道括约肌的随意横纹肌的活动协调。 七种周边反射使这种协调成为可能，所有这些都来自机械提示 在膀胱中（即膀胱伸展）或在尿道中（即尿道流体流动或扩张）。 值得注意的是，我们不知道这些分子的身份，也不知道哪些细胞类型能感受到这些分子。 机械力例如，两种细胞类型，支配LUT的感觉神经元和 膀胱中的尿路上皮细胞被认为有助于这些反射。因此，细节 这些反射是如何启动并整合到系统中的，人们仍然知之甚少。 我假设机械感觉离子通道PIEZO 1和PIEZO 2介导 下尿路的机械感应。我将结合膀胱压力记录 用肌电图来表征排尿反射，以及组织学和行为学， 表征PIEZO在排尿中的表达和功能作用，特别是当它们 在尿路上皮细胞中起作用。我还将测试PIEZO在介导膀胱炎中的作用， 对液体填充的调节反应，以及它们在病理性疼痛期间介导疼痛中的作用。 比如膀胱炎总之，这些结果将描述 机械转导离子通道，特定的细胞类型和外周电路， 小便了解这些过程是减轻巨大的 人类LUT病理学负担。

Project Summary Problems with function in the lower urinary tract (LUT) are remarkably common: in adults over 40, up to 70% of all survey respondents report LUT pathologies. This is in part because the physiology of urination (micturition) is complex: it requires smooth muscle in the bladder and urethra to be coordinated with activity in the voluntary, striated muscle of the urethral sphincter. Seven peripheral reflexes enable this coordination, and all of these arise from mechanical cues in the bladder (i.e. bladder stretch) or in the urethra (i.e. urethral fluid flow or distension). Remarkably, we do not know the identity of the molecules or exactly which cell types sense these mechanical forces. For example, two cell types, sensory neurons that innervate the LUT and the urothelial cells in the bladder, are proposed to contribute to these reflexes. Therefore, the details of how these reflexes are initiated and integrated in the system remain poorly understood. I hypothesize that the mechanosensory ion channels PIEZO1 and PIEZO2 mediate mechanosensing in the lower urinary tract. I will use bladder-pressure recordings in combination with electromyography to characterize micturition reflexes, as well as histology and behavior to characterize the expression and the functional role of PIEZOs in urination, specifically as they function in the urothelial cells. I will also test the role of PIEZOs in mediating bladder accommodation responses to fluid filling, as well as their role in mediating pain during pathological conditions like cystitis. Together, these results will delineate the contribution of the mechanotransduction ion channels, specific cell types and peripheral circuitry that facilitate urination. Understanding these processes is an important first step to alleviate the enormous burden of LUT pathologies in humans.