Molecular mechanisms of mechanosensing in the urinary tract

泌尿道机械传感的分子机制

• 批准号: 10683682
• 负责人: Kara L Marshall
• 金额: $ 24.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683682
• 关键词: Adult; Affect; Afferent Neurons; Animals; Attenuated; Behavior; Behavioral; Biological Assay; Bladder; Calcium; Complex; 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; Persons; 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; mechanical signal; mechanical stimulus; 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.

项目摘要 下尿路（LUT）功能的问题非常普遍：在成年人中 超过40％的受访者中，有40％的人报告了LUT病理。这部分是因为 排尿生理学（排尿）很复杂：需要膀胱中的平滑肌 尿道与尿道括约肌的自愿性肌肉肌肉的活性协调。 七个外围反射可以实现这种协调，所有这些都来自机械提示 在膀胱（即膀胱拉伸）或尿道（即尿道流体流或延伸）中。 值得注意的是，我们不知道分子的身份或确切的细胞类型 机械力。例如，两种细胞类型，即支配LUT的感觉神经元和 提议膀胱中的尿路上皮细胞有助于这些反射。因此，细节 这些反射的启动和整合在系统中的理解仍然很低。 我假设机械感觉离子通道Piezo1和Piezo2介导 下尿路中的机械感应。我将组合使用膀胱压力录音 用肌电图来表征排尿反射，以及组织学和行为 表征压电在排尿中的表达和功能作用，特别是当它们 在尿路上皮细胞中的功能。我还将测试压电在介导膀胱中的作用 对液体填充的适应反应，以及它们在病理学期间介导疼痛中的作用 膀胱炎等疾病。这些结果将共同描述 机械转导离子通道，特定的细胞类型和外围电路 排尿。了解这些过程是减轻巨大的重要第一步 人类的LUT病理负担。