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）：该提案描述了一个为期 5 年的培训计划，旨在为 PI 的长期目标提供一个合适的环境，以发展儿科重症监护领域的独立学术职业。为了确保高度结构化的研究培训，她最近被录取为博士学位。生物化学系研究生课程。该研究项目的总体目标是检验以下假设：血管舒张性休克代表作用于小窝的生理性血管收缩/血管舒张信号系统的病理延伸。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，先前收缩受体刺激对收缩信号传导的下调涉及 Ca2+、tyr- 和 ser/thr 磷酸化依赖性事件。目标 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，包括小凹在此过程中发挥的作用。具体目标 2：初步数据表明，小凹处 rhoA/ROK 信号系统的抑制参与了先前收缩受体刺激产生的下调，并参与了松弛信号系统的激活。数据还表明，这两种刺激都会引起小窝内化。目标 2 将检验以下假设：收缩和舒张的下调反映了收缩信号系统暂时与小窝分离的常见机制。具体目标 3 将检验以下假设：血管平滑肌在血管舒张性休克期间收缩“失败”反映了收缩信号系统与小凹的长期解偶联。在引起血管舒张性休克的基本细胞和分子机制中获得的知识将应用于未来的项目专门了解儿科重症监护室中的休克。临床意义在于，小窝可能代表了导致血管舒张性休克的最终共同途径，了解这些过程可能会导致开发治疗休克的新型治疗药物。