Molecular mechanisms of mechanosensing in the urinary tract

泌尿道机械传感的分子机制

• 批准号: 10192406
• 负责人: Kara L Marshall
• 金额: $ 9.14万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192406
• 关键词: Adult; Affect; Afferent Neurons; Animals; Attenuated; Behavior; Behavioral; Biological Assay; Bladder; Calcium; Complex; Cues; Cystitis; Detection; Electromyography; Excision; Exposure to; Genes; Genetic Models; Health; Histology; Human; Hypersensitivity; Image; Impairment; In Vitro; Ion Channel; Knock-out; Knockout Mice; Liquid substance; Lower urinary tract; Mammals; Mechanics; Mediating; Mediator of activation protein; Medical; Micturition Reflex; Modeling; Molecular; Mus; Nervous system structure; Neurons; Nociceptors; Pain; Pathologic; Pathology; Peripheral; Pharmacology; Physiological; Physiology; Piezo 1 ion channel; Piezo 2 ion channel; Preparation; Process; Reflex action; Reporting; Respondent; Role; Signal Transduction; Signaling Molecule; Smooth Muscle; Stimulus; Stretching; Striated Muscles; Surveys; System; Techniques; Testing; Urethra; Urethral sphincter; Urinary tract; Urination; Urodynamics; Urothelial Cell; Urothelium; Work; bladder pain; cell type; detector; fluid flow; in vivo; mechanical allodynia; mechanical force; mechanotransduction; pain behavior; pain sensation; pressure; response; sensor; urinary; wasting

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.

项目概要 下尿路 (LUT) 功能问题非常常见：在成人中 超过 40 名受访者中，高达 70% 的受访者报告了 LUT 病症。这部分是因为 排尿（排尿）的生理学很复杂：它需要膀胱中的平滑肌和 尿道与尿道括约肌的随意横纹肌的活动相协调。 七种外周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（即膀胱拉伸）或在尿道中（即尿道液流或扩张）。 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够感知这些分子。 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 关于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 PIEZO1 和 PIEZO2 介导 下尿路的机械传感。我将结合使用膀胱压力记录 通过肌电图来表征排尿反射，以及组织学和行为来表征 描述 PIEZO 在排尿中的表达和功能作用，特别是它们 在尿路上皮细胞中发挥作用。我还将测试 PIEZO 在调节膀胱方面的作用 对液体充盈的调节反应，以及它们在病理过程中调节疼痛的作用 膀胱炎等疾病。这些结果将共同描绘出 机械转导离子通道、特定细胞类型和外围电路，促进 排尿。了解这些过程是缓解巨大压力的重要第一步 人类 LUT 病理的负担。