Arterial cell signaling in vasodilatory shock.

描述(由申请人提供)：这份建议书描述了一项为期5年的培训计划，旨在为PI在儿科重症监护领域发展独立学术生涯的长期目标提供合适的环境。为了确保高度结构化的研究培训，她最近被生物化学系的博士研究生项目录取。该研究项目的总体目标是检验这样一种假设，即血管扩张性休克代表作用于小窝的生理血管收缩/血管扩张信号系统的病理性延伸。为了实现这一目标，以下具体目标将测试工作模型。具体目标1：初步数据表明，先前的收缩受体刺激下调收缩信号涉及钙、酪氨酸和丝氨酸/酪氨酸磷酸化依赖的事件。目标1将专门定义参与收缩受体诱导的收缩下调的分子玩家，包括小凹在这一过程中所起的作用。具体目的2：初步数据表明，小窝RhoA/ROK信号系统的抑制既参与了先前收缩受体刺激产生的下调，也参与了松弛信号系统的激活。数据还表明，这两种刺激都会导致腔隙内化。目的2将验证这一假说，即收缩和松弛的下调反映了一种常见的机制，即收缩信号系统暂时脱离小窝。临床意义在于小窝可能是导致血管扩张性休克的最终共同途径，了解这些过程可能会导致开发新的治疗休克的药物。

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.