Regulation of sinusoidal perfusion in shock

休克时正弦灌注的调节

• 批准号: 7849427
• 负责人: MARK G CLEMENS
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849427
• 关键词: Adenoviruses; Affect; Animals; Blood Vessels; Calmodulin 1; Caveolae; Cells; Cholesterol; Complex; Coupling; Cyclodextrins; Defect; Drug or chemical Tissue Distribution; Endothelin; Endothelin-1; Endotoxemia; Endotoxins; Event; Filipin; Funding; Gene Transfer; Hepatic; In Vitro; Inflammatory; Inflammatory Response; Injury; Investigation; Ligation; Liver; Location; Mediating; Microcirculation; Mitogens; Modification; Mus; Nitric Oxide Synthase; Oxidative Stress; Oxygen; Pathway interactions; Perfusion; Progress Reports; Proteins; Puncture procedure; Regulation; Role; Sepsis; Shock; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Stress; Testing; Tissues; Work; clinically relevant; in vivo; insight; overexpression; prototype; receptor; response

Altered hepatic vascular regulation is a common event following shock or sepsis. Recent work shows that this is related to increased constrictor response to endothelin that is associated with decreased eNOS activation. We now hypothesize that inflammatory and oxidative stress associated with shock and sepsis disrupt signaling of endothelin-1 via effects on proteins sequestered in caveolae. The result is uncoupling of ET receptors from eNOS activation, but not from constrictor signaling. Ultimately vascular dysregulation potentiates liver injury and inflammatory response. Given the many signaling molecules that are sequestered in the caveolae, the potential significance of this investigation goes beyond vascular regulation and may provide valuable insights regarding cell signaling in general during shock and sepsis. In order to test this hypothesis, we propose the following aims. Aim 1: Test whether alterations in proteins associated with caveolae is a common pathway in shock related injuries. Aim 2: Test whether changes in basal expression of caveolae-associated proteins result in altered endothelin-1 signaling. Aim 3: Test whether stress-induced changes can be mimicked by manipulation of components of the caveolar domains. Aim 4: Test whether manipulation of mechanisms identified as important in aims 1-3 have a significant impact on vascular regulation, distribution of tissue oxygen and liver injury in vivo. Upon completion of the above aims, we will have elucidated the effect of prototypical in vitro stresses as well as clinically relevant in vivo stresses on regulation of proteins associated with caveolar domains that affect the interaction between endothelin and NO. We will also have determined the functional significance of these changes for endothelin signaling in vitro and for hepatic vascular regulation in vivo. The hepatic microcirculation has many unique aspects; however, there is evidence that these mechanisms with some modifications may be virtually ubiquitous in vascular cells. Thus our findings are likely to have much broader application than just understanding of liver injury during shock states.

肝血管调节改变是冲击或败血症后的常见事件。最近的工作表明 这与与eNOS减少有关的内皮素的收缩反应增加有关 激活。我们现在假设与休克和败血症相关的炎症和氧化应激 通过对小窝隔离的蛋白质的影响，内皮素-1的信号传导。结果是解开 eNOS激活的ET受体，而不是收缩器信号传导。最终的血管失调 增强肝损伤和炎症反应。考虑到许多信号分子 该研究的潜在意义超出了血管调节 并可能在冲击和败血症期间对细胞信号传导提供有价值的见解。为了 检验该假设，我们提出以下目的。目标1：测试是否与蛋白质的改变相关 与Caveolae一起是冲击相关伤害的常见途径。 AIM 2：测试基础是否变化 小窝相关蛋白的表达导致内皮素-1信号传导改变。目标3：测试是否 应力诱导的变化可以通过操纵洞穴结构域的组件来模仿。目标4： 测试操纵在目标1-3中对机制很重要的机制是否具有重大影响 血管调节，组织氧和体内肝损伤的分布。完成上述目标后， 我们将阐明典型的体外应力以及临床相关的体内应力的影响 在调节与洞穴结构域相关的蛋白质，这些蛋白质影响内皮素和 不。我们还将确定这些变化对于内皮素信号传导的功能意义 体内体外和肝血管调节。肝微循环具有许多独特的方面。 但是，有证据表明，这些具有某些修改的机制实际上无处不在 血管细胞。因此，我们的发现可能具有更广泛的应用，而不是了解肝脏 冲击状态期间受伤。