Biology of Tie2 in sepsis

描述（由申请人提供）：Tie-2受体在内皮细胞中高度特异性表达。它在成熟血管中的整体组成性激活被认为介导血管静止。脓毒症是一种常见的疾病，其主要表现涉及血管系统。理论依据：实验性脓毒症中Tie-2的表达和活化均下降，对其组成性信号传导产生“双重打击”。用重组血管生成素-1（Angpt-1，其内源性激动剂配体）或非Angpt-1肽模拟物刺激Tie-2可预防小鼠脓毒症中的多器官功能障碍和死亡。Angpt-2是Tie-2的环境依赖性拮抗剂，在脓毒症个体的循环中升高，与疾病的严重程度成比例，并且循环Angpt-2的早期测量可以预测疑似感染患者的不良结局。尽管有这些有希望的发现，很少有人了解受损的Tie-2的直接局部生理作用 Tie-2及其配体在炎症状态下的调节作用知之甚少。假设：我们推测，受损的Tie-2信号传导可能导致血管渗漏、血管炎症和多器官功能障碍，从而导致脓毒症患者死亡。目的：为了验证这一点，我们提出了3个目标：（1）使用组织特异性四环素诱导的显性阴性Tie-2小鼠来研究局部受损的Tie-2信号传导的急性和慢性后果;（2）应用细胞和啮齿动物炎症模型来鉴定Tie-2表达被抑制的机制;和（3）阐明炎性Angpt-2诱导的机制，其可被目前在危重病群体中评估的药物减弱。研究设计：为了实现这些并行目标，我们设计了细胞机制研究，这些研究将补充我们实验室已经验证的最先进的小鼠遗传模型。这些工具将通过功能获得和丧失实验，为Tie-2的生物学提供前所未有的见解。我们已经组建了一个由败血症研究、啮齿动物生理学、小鼠遗传模型和Tie-2信号传导方面的专家组成的团队来帮助我们。

DESCRIPTION (provided by applicant): The Tie-2 receptor is highly and specifically expressed in endothelial cells. Its global constitutive activation in mature blood vessels is thought to mediate vascular quiescence. Sepsis is a common and morbid disease whose cardinal manifestations involve the vasculature. RATIONALE: Both the expression and activation of Tie-2 fall in experimental sepsis, creating a "double-hit" to its constitutive signalng. Stimulation of Tie-2 with recombinant Angiopoietin-1 (Angpt-1, its endogenous agonist ligand) or non-Angpt-1 peptide mimetics prevents multi-organ dysfunction and death in murine sepsis. Angpt-2, the context-dependent antagonist of Tie-2, is elevated in the circulation of septic individuals in proportion to the severity of disease, and early measurement of circulating Angpt-2 may predict adverse outcomes in patients with suspected infection. Despite these promising findings, little is understood about the direct local physiological contributions of impaired Tie-2 signaling and even less is known about the regulation of Tie-2 and its ligands in states of inflammation. HYPOTHESIS: We hypothesize that impaired Tie-2 signaling may contribute to the vascular leakage, vascular inflammation, and multi-organ dysfunction that contribute to death in sepsis. AIMS: To test this, we propose 3 aims: (1) using tissue-specific tetracycline-inducible dominant-negative Tie-2 mice to study the acute and chronic consequences of locally impaired Tie-2 signaling; (2) applying cellular and rodent models of inflammation to identify mechanisms through which Tie-2 expression is suppressed; and (3) elucidating a mechanism of inflammatory Angpt-2 induction that may be attenuated by drugs currently being evaluated in critically ill populations. RESEARCH DESIGN: To execute these parallel aims, we have designed cellular mechanistic studies that will complement state-of-the-art mouse genetic models already validated in our laboratory. These tools will provide unprecedented insights into the biology of Tie-2 through gain- and loss-of-function experiments. We have assembled a team of experts in sepsis research, rodent physiology, mouse genetic models, and Tie-2 signaling to assist us.