The Role of Inflammation in Ischemic Organ Injury

描述（由申请人提供）：本研究探讨toll样受体2 （TLR2）介导的信号在小鼠肾缺血再灌注（IR）损伤模型中的作用。实验性肾IR损伤模拟缺血性急性肾损伤，后者是住院患者发病和死亡的主要原因。待验证的总体假设是，TLR2通过直接和/或间接促进肾小管细胞损伤，在肾IR损伤的发病机制中起主要作用。具体目的：(1)确定tlr2介导的信号是否直接损伤小管上皮细胞，明确细胞损伤的机制；(2)确定TLR2结扎是否通过直接（局部）或间接（全身）作用导致IR损伤；(3)确定TLR2结扎是否通过激活适应性免疫导致IR损伤。意义：缺血再灌注损伤是住院患者急性肾功能衰竭的常见原因，与发病率和死亡率的增加直接相关。尽管进行了广泛的研究，肾脏损伤的机制仍然难以捉摸，更重要的是，除了支持性护理之外，没有有效的预防方案或治疗方法。认识到缺血组织通过tlr释放触发组织损伤的分子开辟了一个新的研究领域。PI的实验室发现，一种TLR， TLR2，在肾脏对肾IR损伤最敏感的区域高度表达。如果发现TLR2在肾IR损伤的局部或全身阶段都是关键参与者，那么TLR2定向策略将被用于缺血性肾损伤的预防和治疗。

DESCRIPTION (provided by applicant): The study examines the role of toll-like receptor 2 (TLR2)-mediated signals in a murine model of renal ischemia reperfusion (IR) injury. Experimental renal IR injury mimics ischemic acute kidney injury, a major cause of morbidity and mortality in hospitalized patients. The overall HYPOTHESIS to be tested is that TLR2 plays a primary role in the pathogenesis of renal IR injury by directly and/or indirectly contributing to renal tubular cell injury. Specific Aims: (1) Determine whether TLR2-mediated signals directly injure tubular epithelial cells and define the mechanisms of cell injury; (2) Determine whether TLR2 ligation contributes to IR injury through direct (local) or indirect (systemic) effects; (3) Determine whether TLR2 ligation contributes to IR injury through activation of adaptive immunity. Significance: Ischemia reperfusion injury is a common cause of acute renal failure in hospitalized patients and is directly linked to an increase in morbidity and mortality. Despite extensive research, the mechanisms of renal injury remain elusive and more importantly there are no effective prophylactic regimens or treatments for established disease, other than supportive care. Recognition that ischemic tissue releases molecules that trigger tissue injury through TLRs has opened a new field of research. The PI's laboratory has found that one TLR, TLR2, is highly expressed in the region of the kidney that is most sensitive to renal IR injury. If TLR2 is found to be the key participant in either local or systemic phases of renal IR injury, then TLR2 directed strategies would be pursued for both prophylaxis and treatment of ischemic renal injury.