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.

肝血管调节改变是休克或败血症后的常见事件。最近的工作表明 这与收缩肌对内皮素的反应增加有关，而内皮素又与 eNOS 减少有关 激活。我们现在假设炎症和氧化应激与休克和败血症相关 通过影响小窝中隔离的蛋白质来破坏内皮素-1 的信号传导。结果是解耦 ET 受体来自 eNOS 激活，但不来自缩窄信号传导。最终导致血管失调 增强肝损伤和炎症反应。鉴于许多信号分子 隔离在小窝中，这项研究的潜在意义超出了血管调节的范围 并可能提供有关休克和脓毒症期间细胞信号传导的有价值的见解。为了 检验这个假设，我们提出以下目标。目标 1：测试蛋白质的改变是否相关 小凹是休克相关损伤的常见途径。目标2：测试基础值是否发生变化 小凹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 压力引起的变化可以通过操纵小窝区域的成分来模拟。目标 4： 测试目标 1-3 中确定的重要机制的操纵是否会对 血管调节、组织氧分布和体内肝损伤。完成上述目标后， 我们将阐明典型的体外应激以及临床相关的体内应激的影响 与小凹结构域相关的蛋白质的调节，影响内皮素和内皮素之间的相互作用 不。我们还将确定这些变化对内皮素信号传导的功能意义 体外和体内肝血管调节。肝脏微循环有许多独特的方面； 然而，有证据表明，经过一些修改的这些机制实际上可能普遍存在于 血管细胞。因此，我们的发现可能具有更广泛的应用，而不仅仅是了解肝脏 休克状态下受伤。