The Role of Inflammation in Ischemic Organ Injury

炎症在缺血性器官损伤中的作用

• 批准号: 8214657
• 负责人: Dianne B Mckay
• 金额: $ 19.46万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214657
• 关键词: Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; Agonist; Apoptosis; Area; Blocking Antibodies; Breeding; Critiques; Data; Disease; Distal; Epithelial Cells; Epithelium; Experimental Designs; Future; Generations; Genetic; Genotype; Germ-Free; Goals; Human; Hypoxia; Inflammation; Inflammatory Response; Injury; Kidney; Laboratories; Ligands; Ligation; Link; Mediating; Mediator of activation protein; Mind; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Necrosis; Organ; Outcome; Paper; Participant; Pathogenesis; Patients; Phase; Play; Principal Investigator; Process; Prophylactic treatment; Published Comment; Publishing; Regimen; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resources; Role; Signal Transduction; Skin; Suggestion; Supportive care; Surface; TNF gene; TNFSF5 gene; Testing; Therapeutic; Tissues; Toll-Like Receptor 2; Toll-like receptors; Transplantation; Tubular formation; adaptive immunity; caspase-3; cell injury; design; experience; in vivo; injured; insight; interest; interstitial; kidney epithelial cell; mortality; programs; prophylactic; protective effect; renal ischemia; research study; response

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.

描述（由申请人提供）：研究检查了类似收费的受体2（TLR2）介导的信号在肾脏缺血再灌注（IR）损伤的鼠模型中的作用。实验性肾脏IR损伤模仿缺血性急性肾脏损伤，这是住院患者发病率和死亡率的主要原因。要测试的总体假设是，TLR2通过直接和/或间接促进肾小管细胞损伤而在肾脏IR损伤的发病机理中起主要作用。具体目的：（1）确定TLR2介导的信号是否直接损害管状上皮细胞并定义细胞损伤的机制； （2）确定TLR2连接是否通过直接（局部）或间接（全身）效应造成IR损伤； （3）确定TLR2连接是否通过激活适应性免疫有助于IR损伤。意义：缺血再灌注损伤是住院患者急性肾衰竭的常见原因，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，但除支持性护理以外，肾脏损伤的机制仍然难以捉摸，更重要的是，没有有效的预防治疗方案或治疗已建立疾病的治疗方法。认识到缺血组织释放通过TLR引发组织损伤的分子已开辟了一个新的研究领域。 PI的实验室发现，一个TLR TLR2在肾脏最敏感的肾脏IR损伤的区域中高度表达。如果发现TLR2是肾脏IR损伤的局部或全身阶段的关键参与者，则将针对预防和治疗缺血性肾脏损伤的TLR2指示策略。