How is Fullness Sensed in the Urinary Bladder?

如何感觉到膀胱充盈？

• 批准号: 10413220
• 负责人: Thomas Heppner
• 金额: $ 43.78万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413220
• 关键词: 3-Dimensional; Address; Affect; Algorithms; Attention; Basic Science; Behavior; Bladder; Bladder Dysfunction; Brain; Cations; Clinical; Conscious; Coupling; Data; Disease; Event; Fibroblasts; Future; Genetic; Giant Cells; Goals; Grant; Heart; Image; Image Analysis; Imaging Techniques; Ion Channel; Knockout Mice; Lead; Life; Liquid substance; Lower urinary tract; Measures; Mediating; Methodology; Modeling; Mus; Nerve; Neuraxis; Output; Overactive Bladder; Pain; Pathology; Pharmacology; Physiological; Physiological Processes; Piezo 1 ion channel; Piezo 2 ion channel; Piezo ion channels; Process; Property; Regulation; Reporter; Reporting; Role; Sensory; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stretching; Surface; System; Techniques; Time; Translating; Urine; Urodynamics; Urothelial Cell; Urothelium; Work; afferent nerve; cell motility; cell type; comparative; in vivo; insight; interstitial cell; intravesical; mechanical properties; mechanotransduction; mouse model; novel; novel imaging technique; optogenetics; pressure; real time monitoring; response; signal processing; tool; 3-Dimensional; Address; Affect; Algorithms; Attention; Basic Science; Behavior; Bladder; Bladder Dysfunction; Brain; Cations; Clinical; Conscious; Coupling; Data; Disease; Event; Fibroblasts; Future; Genetic; Giant Cells; Goals; Grant; Heart; Image; Image Analysis; Imaging Techniques; Ion Channel; Knockout Mice; Lead; Life; Liquid substance; Lower urinary tract; Measures; Mediating; Methodology; Modeling; Mus; Nerve; Neuraxis; Output; Overactive Bladder; Pain; Pathology; Pharmacology; Physiological; Physiological Processes; Piezo 1 ion channel; Piezo 2 ion channel; Piezo ion channels; Process; Property; Regulation; Reporter; Reporting; Role; Sensory; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stretching; Surface; System; Techniques; Time; Translating; Urine; Urodynamics; Urothelial Cell; Urothelium; Work; afferent nerve; cell motility; cell type; comparative; in vivo; insight; interstitial cell; intravesical; mechanical properties; mechanotransduction; mouse model; novel; novel imaging technique; optogenetics; pressure; real time monitoring; response; signal processing; tool

SUMMARY In normal day-to-day life, the sense of urinary bladder fullness is conveyed to the central nervous system such that voiding of urine is not too frequent, and retaining urine is not too painful. Much attention has focused on attempting to treat urinary bladder dysfunctions however, to understand any disorder of the lower urinary tract an essential physiological question must be addressed, and that is: How is bladder fullness sensed? Amazingly, the basic physiological mechanisms for sensing bladder fullness remain elusive. Exploring this fundamental question will be the focus of the current proposal, which should deepen our understanding of this process, providing important insights into the fundamental mechanisms involved in translating bladder fullness into afferent information. We propose the novel overarching concept that local changes in mechanical properties of the urinary bladder wall during filling are what drives sensory outflow. Importantly, pressure, per se, does not drive afferent nerve activity. Rather, it is the local deformation of the bladder wall that is the stimulus for afferent nerve activity. During filling, local excitation of detrusor smooth muscle (DSM) spreads spatially to cause small transient contractions of the bladder wall, called micromotions. Micromotions lead to angular distortions and localized changes in wall tension of the bladder wall. It is this localized change in wall tension that we believe triggers afferent nerve activity to sense bladder filling. This proposal gets at the heart of determining how fullness is sensed in the urinary bladder, without speculating about cell types involved in signaling (urothelial cells, interstitial cells, fibroblasts, etc). This project utilizes numerous novel techniques and approaches, such as our pentaplanar reflected image macroscopy platform that enables real-time monitoring of micromotions on the entire surface of the bladder. We have devleoped cutting edge imaging methodologies and signal processing algorithms to quantify bladder motility and Ca2+ signaling dynamcis. In Aim 1, we will determine the basis for local excitation of DSM during bladder filling. We will use imaging techniques on mice expessing genetically encoded Ca2+ indicators to study how the excitatiliby of the DSM affects the spatial spread of Ca2+ signals. Aim 2 explores spatial-temporal relationships between excitation and the rate/extent of angular distortions, and afferent nerve activity during filling. We will use simultaneous recordings of DSM Ca2+ activity, bladder pressure and afferent nerve activity. Finally, in Aim 3, we will investigate the basis for mechano-sensing by afferent nerves in the urinary bladder and the role of Piezo1 and Piezo2 stretch-sensitive cation channels. Importantly, we will characterize bladder function in Piezo2 knockout mice in vivo. Through completion of this project, we will gain fundamental insights into the mechanisms whereby physical forces during filling are sensed by the urinary bladder. Once we gain a full understanding of these processeses, we will be better suited to model, study, and treat bladder dysfunctions.

概括 在正常的日常生活中，尿液膀胱饱满感被传达给中枢神经系统 尿液的空隙不太频繁，保留尿液并不痛苦。非常关注 但是，试图治疗膀胱功能障碍，以了解下尿路的任何疾病 必须解决一个基本的生理问题，也就是说：膀胱饱满感如何感觉到？ 令人惊讶的是，感测膀胱饱满的基本生理机制仍然难以捉摸。探索这个 基本问题将是当前建议的重点，这应该加深我们对此的理解 流程，提供对翻译膀胱饱满的基本机制的重要见解 进入传入信息。我们提出了新的总体概念，即机械性能的局部变化 在填充过程中，膀胱壁是驱动感官流出的原因。重要的是，压力本身不会 驱动传入神经活动。相反，膀胱壁的局部变形是传入的刺激 神经活动。在填充过程中，局部激发逼尿肌平滑肌（DSM）在空间上扩散以引起很小的 膀胱壁的瞬态收缩，称为微动。微动物导致角畸变和 膀胱壁的壁张力的局部变化。我们相信，正是墙壁紧张的局部变化 触发神经活动以感知膀胱填充。该提议是确定多么饱满的核心 在膀胱中感测，而没有猜测涉及信号传导的细胞类型（尿路上皮细胞， 间质细胞，成纤维细胞等）。该项目利用了许多新颖的技术和方法，例如我们 Pentaplanar反射的图像宏观镜检查平台，可以实时监视整个微型 膀胱的表面。我们已经开阔了尖端成像方法和信号处理 量化膀胱运动和Ca2+信号动态的算法。在AIM 1中，我们将确定 膀胱填充期间DSM的局部激发。我们将在遗传上使用的小鼠上使用成像技术 编码的CA2+指标研究了DSM的激励如何影响Ca2+信号的空间扩散。目的 2探索激发与角畸变的速率/程度之间的时空关系， 填充过程中的传入神经活动。我们将同时使用DSM Ca2+活动，膀胱压力的记录 和传入的神经活动。最后，在AIM 3中，我们将研究传入神经的机械感应基础 在膀胱以及压电和压电伸展敏感阳离子通道的作用中。重要的是，我们会的 在体内表征Piezo2敲除小鼠中膀胱功能。通过完成该项目，我们将获得 尿液中填充过程中物理力的机制的基本见解 膀胱。一旦我们对这些过程有充分的了解，我们将更适合建模，学习和 治疗膀胱功能障碍。