Arterial cell signaling in vasodilatory shock.

描述（由申请人提供）：本提案描述了一项为期5年的培训计划，旨在为PI的长期目标提供适当的环境，以发展儿科重症监护的独立学术生涯。为了确保高度结构化的研究培训，她最近被博士学位录取。生物化学系的研究生课程。该研究项目的总体目标是检验血管舒张性休克是生理性血管收缩/血管舒张信号系统作用于小窝的病理延伸的假设。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对收缩信号的下调涉及Ca 2+、tyr-和ser/thr磷酸化依赖性事件。目的1将具体定义参与收缩受体诱导的收缩下调的分子参与者，包括小窝在这一过程中发挥的作用。具体目标2：初步数据表明，在小窝的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，并在松弛信号系统的激活。数据还表明，这两种刺激引起小窝内化。目的2将测试这一假设，即下调的收缩和放松反映了一个共同的机制，其中收缩信号系统是暂时解耦的小窝。具体目标3将检验这一假设，即血管舒张性休克时血管平滑肌收缩的“失败”反映了收缩信号系统与caveolae.The知识的基础细胞和分子机制，导致血管舒张性休克将被应用到未来的项目，特别是了解休克在儿科重症监护环境中的解偶联。临床意义在于，小窝可能代表负责血管舒张性休克的最终共同途径，并且理解这些过程可能导致开发新的治疗剂来治疗休克。

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.