Smooth Muscle, Differential Tissue Function & Diabetes

描述(由申请人提供)： 我们计划的主题是研究生理上不同的器官系统中对平滑肌细胞张力的差异性控制。多学科方法将确保在细胞和分子水平上获得的信息将在组织响应在体外和体内器官中如何协调的背景下得到解释。我们的假设是，不同的器官功能，因为它与膀胱和阴茎的肌细胞生理有关，可归因于离子机制参与肌细胞张力控制(即收缩和松弛)的方式的可量化差异。此外，我们假设糖尿病相关的神经和/或心肌细胞生理学改变将不同地导致膀胱和勃起功能障碍。为此，我们将使用两种成熟的糖尿病神经病变大鼠模型，分别是链脲佐菌素(STZ)和生物育种伍斯特(BB/W)。该计划的目标是获得一个全面的膀胱和勃起功能图，以及糖尿病神经病变/肌肉病变对尿失禁和阳萎的贡献。项目1将在同一动物体内评估膀胱和勃起功能以及肌细胞张力。在活体研究之后，膀胱和勃起组织将在项目2到4之间细分。项目2将在组织和单细胞水平进一步表征肌细胞张力。项目#3将研究心肌细胞对之间离子信号在细胞间传递的特性和调节，以及它们对心肌细胞反应协调的贡献。项目#4将描述通过细胞间和细胞外途径协调的心肌细胞钙信号机制的关键贡献。A和B核心将分别提供行政和动物支助服务。Core C公司将为项目的每个组成部分独一无二地实施数学模型，定量描述和预测观察到的膀胱和阴茎在分子、细胞、组织或器官功能方面的差异，以及STZ糖尿病对这些过程的影响。该计划的意义在于，它将勾勒出不同器官功能的机制，为糖尿病神经病变对常见的泌尿系统并发症的贡献提供新的见解，并提出新的治疗可能性。

DESCRIPTION (provided by applicant): The theme of our Program focuses on studying the differential control of smooth muscle cell tone in physiologically distinct organ systems. A multidisciplinary approach will ensure that information obtained at the cellular and molecular levels will be interpreted in the context of how tissue responses are coordinated in organs in vitro and in vivo. Our hypothesis is that differential organ function, as it relates to myocyte physiology in the bladder and penis, is attributable to quantifiable differences in the way that ionic mechanisms participate in the control of myocyte tone (i.e., contraction and relaxation). Additionally we hypothesize that diabetes-related alterations in neural and/or myocyte physiology will differentially contribute to bladder and erectile dysfunction. To this end, we will use two well-established rat models of diabetic neuropathy, the Streptozotocin (STZ) and BioBreeding Worcester (BB/W), respectively. The Program goal is to obtain a comprehensive functional map of bladder and erectile function, as well as the contribution of diabetic neuropathy/myopathy to urinary incontinence and impotence. Project #1 will evaluate bladder and erectile function and myocyte tone in vivo, in the same animal. Following the in vivo studies, bladder and erectile tissues will be subdivided between Projects 2 to 4. Project #2 will further characterize myocyte tone at the tissue and single cell level. Project #3 will study the properties and regulation of the intercellular transmission of ionic signals among myocyte cell pairs, and their contribution to coordination of myocyte responses. Project #4 will characterize the critical contribution of coordinated myocyte calcium signaling mechanisms via intercellular and extracellular pathways. Cores A & B will provide administrative and animal support services, respectively. Core C will uniquely implement mathematical models for each of the Project components that quantitatively describe and predict the observed distinctions in molecular, cellular, tissue or organ function between the bladder and penis, as well as the effects of STZ-diabetes on these processes. The significance of the Program is that it will delineate mechanisms of differential organ function, shed new insight on the contribution of diabetic neuropathy to commonly observed urologic complications, and suggest novel therapeutic possibilities.