How is Fullness Sensed in the Urinary Bladder?

如何感觉到膀胱充盈？

基本信息

批准号：
10034865
负责人：
Thomas Heppner
金额：
$ 48万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
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/10034865
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

项目摘要

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，膀胱充盈感会传递到中枢神经系统，例如排尿不会太频繁，留尿也不会太痛苦。很多注意力都集中在然而，尝试治疗膀胱功能障碍，了解下尿路的任何疾病必须解决一个基本的生理问题，即：如何感知膀胱充盈度？令人惊讶的是，感知膀胱充盈度的基本生理机制仍然难以捉摸。探索这个根本问题将是当前提案的重点，这应该加深我们对此的理解过程，提供了有关膀胱充盈度转化的基本机制的重要见解转化为传入信息。我们提出了新的总体概念，即机械性能的局部变化充盈期间膀胱壁的变化是驱动感觉流出的原因。重要的是，压力本身并不驱动传入神经活动。相反，膀胱壁的局部变形是传入神经的刺激。神经活动。在充盈过程中，逼尿肌平滑肌 (DSM) 的局部兴奋在空间上传播，导致小膀胱壁的短暂收缩，称为微运动。微动会导致角度扭曲膀胱壁壁张力的局部变化。我们相信，正是壁张力的这种局部变化触发传入神经活动来感知膀胱充盈。该提案的核心是确定丰满度如何在膀胱中被感知，无需推测参与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，例如我们的五平面反射图像肉眼观察平台，可实时监测整个物体的微运动膀胱表面。我们开发了尖端的成像方法和信号处理量化膀胱运动和 Ca2+ 信号动态的算法。在目标 1 中，我们将确定以下基础：膀胱充盈期间 DSM 的局部兴奋。我们将使用成像技术对表达基因的小鼠进行成像编码 Ca2+ 指标来研究 DSM 的兴奋性如何影响 Ca2+ 信号的空间传播。目的 2 探讨了激励与角度扭曲率/程度之间的时空关系，以及充盈期间的传入神经活动。我们将使用 DSM Ca2+ 活性、膀胱压力的同步记录和传入神经活动。最后，在目标 3 中，我们将研究传入神经机械传感的基础膀胱中 Piezo1 和 Piezo2 拉伸敏感阳离子通道的作用。重要的是，我们将表征 Piezo2 敲除小鼠的体内膀胱功能。通过本项目的完成，我们将获得对充盈过程中物理力被尿液感知的机制的基本见解膀胱。一旦我们充分了解这些过程，我们将更适合建模、研究和治疗膀胱功能障碍。