The Role of Inflammation in Ischemic Organ Injury

Scripps Research Institute, The, La Jolla CA

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Abstract

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.