Bladder Blood Flow and Vascular Contractility Regulate Bladder Function

 描述(由申请人提供)：本建议书描述了一项为期5年的下尿路生理学学术发展计划。该候选人拥有平滑肌生理学背景，并在斯蒂芬妮·瓦茨博士和威廉·杰克逊博士(密歇根州立大学)的指导下完成了药理学和毒理学的博士培训。然后，他以博士后身份来到佛蒙特州大学，开始了一条独立研究生涯的道路。他现在结合了他在平滑肌生理学和血管药理学方面的优势，创建了一个新的方案，研究膀胱血流与糖尿病患者膀胱功能障碍的关系。近一半的糖尿病患者经历了下尿路症状(LUTS)，这些症状显著降低了他们的生活质量。尽管有大量证据表明膀胱血流受损与LUTS有关，但我们对膀胱血流调节及其对膀胱功能的影响的认识存在着根本的差距。这个项目的目标是了解膀胱血管的独特性质如何调节膀胱功能。此外，该项目将调查糖尿病患者血流量减少是否会导致膀胱功能障碍，特别关注调节膀胱小动脉血管张力的信号机制。这一假设驱动的研究项目将使申请者能够发展最先进的体外和体内生理学方法，包括电生理学、分离血管的直径和膜电位测量，以及体内尿动力学测量，这将提供糖尿病期间膀胱血管功能的前所未有的详细信息。结果可能是潜在的 重组LUTS治疗，包括血管和神经治疗干预。佛蒙特大学(UVM)在血管和膀胱生理学方面拥有独特的专业知识，在平滑肌生物学方面的实力在国际上得到了认可。马克·纳尔逊博士将指导候选人的科学发展。纳尔逊博士是血管生物学和膀胱生理学领域公认的领导者，培养了许多博士后研究员和研究生，其中许多人现在是知名的独立调查人员。为了加强候选人的培训，该项目邀请了一个指导委员会的专业人士，其中包括约瑟夫·布雷登博士、乔治·威尔曼博士、玛格丽特·维扎德博士和马克·普兰特博士。布雷登博士开创了研究血管平滑肌膜电位的技术。威尔曼博士补充了K通道功能和电生理学方面的专业知识。Vizzard博士在膀胱研究和体内有意识的膀胱测压方面拥有丰富的经验。普兰特博士是一位成功的临床泌尿科医生，在翻译科学和研究方面有自己的见解。这种研究环境最大限度地增加了候选人建立一个科学利基的潜力，从这个利基上可以建立一个学术生涯。该项目将促进对候选人的持续技术、智力和专业培训，并将协助候选人在学术研究机构建立一个独立的研究实验室。

 DESCRIPTION (provided by applicant): This proposal describes a 5-year program for the development of an academic career in lower urinary tract physiology. The Candidate has a background in smooth muscle physiology, and completed doctoral training in Pharmacology and Toxicology under the mentorship of Drs. Stephanie Watts and William Jackson (Michigan State University). He then came to the University of Vermont as a Postdoctoral Fellow to begin a path toward an independent research career. He now combines his strengths in smooth muscle physiology and vascular pharmacology to create a novel proposal investigating bladder blood flow as it relates to bladder dysfunction in diabetes. Nearly half of all diabetic patients experience lower urinary tract symptoms (LUTS), which significantly reduce their quality of life. Although ample evidence links impaired bladder blood flow to LUTS, a fundamental gap exists in our understanding of bladder blood flow regulation and its effects on bladder function. The goals of this project are to understand how the unique properties of the urinary bladder vasculature regulate bladder function. Furthermore, this project will investigate if decreased blood flow leads to bladder dysfunction in diabetes, with a specific focus on signaling mechanisms that regulate vessel tone in bladder arterioles. This hypothesis-driven research project will allow the applicant to develop skills in state-of- the art in vitro and in vivo physioogy methods, including electrophysiology, diameter and membrane potential measurements in isolated blood vessels, and in vivo urodynamic measurements, that will provide unprecedented detail into vascular function in the urinary bladder during diabetes. The results could potentially re-frame LUTS treatment to include both vascular and neurological therapeutic interventions. The University of Vermont (UVM) is internationally recognized for its strength in smooth muscle biology, with unique expertise in both vascular and urinary bladder physiology. Mark Nelson, Ph.D. will mentor the Candidate's scientific development. Dr. Nelson is a recognized leader in the field of vascular biology and bladder physiology and has trained numerous postdoctoral fellows and graduate students, many of whom are now established independent investigators. To enhance the Candidate's training, the program enlists the expertise of a mentoring committee, including Drs. Joseph Brayden, George Wellman, Margaret Vizzard and Mark Plante. Dr. Brayden pioneered techniques for the study of vascular smooth muscle membrane potential. Dr. Wellman adds expertise in K+ channel function and electrophysiology. Dr. Vizzard brings substantial experience with bladder research and in vivo conscious cystometry. Dr. Plante is a successful clinical urologist with perspectives on translational science and research. This research environment maximizes the potential for the Candidate to establish a scientific niche from which an academic career can be constructed. This project will facilitate continued technical, intellectual, and professional training of the Candidate, and will assist the Candidate in the establishment of an independent research laboratory at an academic research institution.