PKC ALTERATIONS IN LUT DYSFUNCTION

LUT 功能障碍中的 PKC 改变

• 批准号: 6500943
• 负责人: Firouz Daneshgari
• 金额: $ 9.02万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500943
• 关键词: biological signal transduction; calcium; carbachol; diabetes mellitus; disease /disorder model; genetically modified animals; isoproterenol; laboratory rat; muscle contraction; parasympathetic nervous system; protein kinase C; smooth muscle; urinary bladder disorder; urinary tract obstruction; urination disorder

This is a revised proposal of the training and research program to support Dr. Firouz Daneshgari for a mentored clinical scientist development award (K08). The proposal will address the pathophysiology of urinary incontinence and voiding dysfunction (UI and VD). UI and VD is a significant and growing medical, social and financial problem in the U.S. Diabetes mellitus (DM), bladder outlet obstruction (BOO), and many other common pathologic conditions with UI and VD, with idiopathic, neuropathic and obstructive etiologies, cause similar structural and possible molecular changes with resultant dysfunction of the lower urinary tract (LUT) smooth muscle/tissue. In many tissues of human and animals, protein kinase C (PKC) has been recognized as a prominent intracellular signaling pathway that mediates responses to various physiologic stimuli and pathologic injuries. PKCmodulates both acute changes in tissue, as well as chronic adaptive changes that can lead to growth, apoptosis or differentiation. The global scientific goal of this application is to interrogate the relationships between DM (a transgenic rat model of type-I like DM), BOO, and chronic parasympathetic blockade and LUT function as assessed by alterations in contractile and relaxing responses detected by in vivo, in vitro, and LUT specific PKC isoforms profile. We propose that the pattern of LUT dysfunction in BOO or diabetes in rat will be replicated by chronic parasympathetic blockade. We further hypothesize that uropathic or mechanical causes of LUT dysfunction will be characterized by alteration in spatial and temporal profile of intracellular LUT protein kinase C isoforms. Base on an outstanding tract record, in both training new investigators and in scientific accomplishments, two groups of experienced scientists at UCHSC, headed by Dr. Alden H. Harken, and at UTSW, headed by Dr. John D. McConnell, will guide and assist Dr. Daneshgari in the development of necessary and sufficient scientific and technical skills to accomplish the specific aims of this application. These groups are uniquely qualified to study the LUT dysfunction and to track altered LUT cell receptor signals into the cystosolic milieu in the normal and abnormal rat. The ultimate goals of this application are : I) to identify intracellular signal transduction events and their mechanism(s) of action, in the LUT, at major transitional events. Replication of PKC isoform profiles among the experimentally pathologic conditions will serve as the mechanistic basis for targeting future treatment strategies, II) to provide the opportunity for Dr. Daneshgari to become an independent investigator in the field of UI and VD, and III) to encourage and to facilitate recruitment of new scientists and new investigative methods, from other fields of biomedical sciences, into the area of investigative urology.

这是培训和研究计划的修订建议，旨在为Firouz Daneshgari博士提供指导的临床科学家发展奖（K08）。 该提案将解决尿失禁和失效功能障碍（UI和VD）的病理生理。 在美国糖尿病（DM），膀胱出口阻塞（BOO）以及许多其他常见病理状况，用UI和VD进行了UI和VD，具有特发性，神经性病理学和阻塞性病理学，带有相似的结构和可能的分子变化（可能会导致幼虫）的分子变化（Lutter n uttriary n utrutional n utrutional n urut ure ure ure ure ure ure utiralient，ui和vd是一个较低的病理状况，UI和VD是一个重大且不断增长的医学，社会和财务问题，以及许多其他常见的病理状况。 在人类和动物的许多组织中，蛋白激酶C（PKC）被认为是一种突出的细胞内信号传导途径，可介导对各种生理刺激和病理损伤的反应。 PKCMODSTOS可以使组织的急性变化以及慢性自适应变化，这可能导致生长，凋亡或分化。该应用的全球科学目标是审问DM（类型I类型的DM类转基因大鼠模型），BOO的转基因大鼠模型和慢性副交感神经封锁和LUT功能，并通过收缩的变化和在体内检测到的放松反应的变化以及LUT特定的PKC同工型评估。 我们提出，BOO或大鼠糖尿病中LUT功能障碍的模式将通过慢性副交感神经阻滞来复制。 我们进一步假设LUT功能障碍的尿道疗法或机械原因将以改变细胞内LUT蛋白激酶C同工型的空间和时间分布的改变。基于培训新的研究人员和科学成就的杰出记录，由Alden H. Harken博士领导的UCHSC的两组经验丰富的科学家以及由John D. McConnell博士领导的UTSW，将指导和协助Daneshgari博士，并协助Daneshgari博士开发必要的科学和技术技能，以实现该应用程序的特定目标。 这些组具有独特的资格研究LUT功能障碍，并在正常和异常大鼠中跟踪变化的LUT细胞受体信号到囊肿环境中。 该应用的最终目标是：i）确定在重大过渡事件中，在LUT中，在LUT中确定细胞内信号转导事件及其作用机制。实验性病理状况之间PKC同工型的复制将是针对未来治疗策略的机械基础，ii）为Daneshgari博士提供了在UI和VD领域成为独立研究者的机会，以及III III），以及III），并促进了新科学家和新研究方法的招聘方法，从其他领域进行了研究，从其他领域进行了研究。