Arterial cell signaling in vasodilatory shock.

血管舒张休克中的动脉细胞信号传导。

• 批准号: 7150135
• 负责人: MELISSA C EVANS
• 金额: $ 13.51万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150135
• 关键词: biological signal transduction; cGMP dependent protein kinase; calcium flux; caveolas; cell surface receptors; electron microscopy; gene induction /repression; guanine nucleotide binding protein; laboratory rabbit; muscle contraction; muscle relaxation; pathologic process; phosphorylation; receptor expression; shock; vascular smooth muscle; vasoconstriction; vasodilation; western blottings

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program designed to provide an environment appropriate for the PI's long-term goal to develop an independent academic career in Pediatric Critical Care. To ensure highly structured research training, she was recently accepted into the Ph.D. graduate program in the Department of Biochemistry. The overall goal of the research project is to test the hypothesis that vasodilatory shock represents a pathological extension of the physiological vasoconstrictor/vasodilatory signaling systems acting at caveolae. To accomplish this goal, the following specific aims will test the working model. Specific aim 1: Preliminary data suggest that down-regulation of contractile signaling by prior contractile receptor stimulation involves Ca2+, tyr-,and ser/thr phosphorylation-dependent events. Aim 1 will specifically define the' molecular players involved in contractile receptor-induced down-regulation of contraction, including the role that caveolae play in this process. Specific aim 2: Preliminary data suggest that inhibition of the rhoA/ROK signaling system at caveolae participates in both down-regulation produced by prior contractile receptor stimulation, and in activation of relaxant signaling systems. The data also suggest that both stimuli cause caveolar internalization. Aim 2 will test the hypothesis that down-regulation of contraction and relaxation reflect a common mechanism in which contractile signaling systems are temporary uncoupled from caveolae. Specific aim 3 will test the hypothesis that "failure" of vascular smooth muscle to contract during vasodilatory shock reflects prolonged uncoupling of contractile signaling systems from caveolae.The knowledge gained in basic cellular and molecular mechanisms causing vasodilatory shock will then be applied to a future project to specifically understand shock in the pediatric intensive care setting. The clinical significance is that caveolae may represent the final common pathway responsible for vasodilatory shock, and understanding these processes may lead to the development of novel therapeutic agents to treat shock.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，旨在提供适合PI长期目标的环境，以开发儿科重症监护领域的独立学术生涯。为了确保高度结构化的研究培训，她最近被接受了博士学位。生物化学系研究生课程。研究项目的总体目的是检验以下假设：血管舒张冲击代表了作用于Caveolae的生理血管收缩剂/血管舒张信号系统的病理扩展。为了实现这一目标，以下特定目标将测试工作模型。具体目的1：初步数据表明，先前的收缩受体刺激对收缩信号的下调涉及Ca2+，Tyr-和Ser/Thr磷酸化依赖性事件。 AIM 1将专门定义与收缩受体诱导的收缩下调有关的分子参与者，包括Caveolae在此过程中扮演的角色。具体目的2：初步数据表明，Caveolae的RhoA/ROK信号系统的抑制参与了先前的收缩受体刺激产生的下调，并激活了松弛信号传导系统。数据还表明两种刺激都会引起洞穴内在化。 AIM 2将检验以下假设：收缩和放松的下调反映了一种共同的机制，即收缩信号系统暂时与小窝解偶联。具体目标3将检验以下假设：血管舒张性休克期间血管平滑肌的“失败”反映了Caveolae的收缩信号系统的延长耦合。在基本的细胞和分子机制中获得的知识将使血管舒张性减震器获得，从而将未来的项目应用于未来的项目，以在良好的养生过程中特定理解震荡。临床意义在于，小窝可能代表导致血管舒张休克的最终常见途径，并且了解这些过程可能会导致新型治疗剂的发展以治疗休克。