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TLR Signaling in Ischemic Myocardial InjurySignaling via Toll-like receptors (TLRs) is a critical component of the innate immune system and represents the first line of host defense against microbial infection. TLRs recognize invading pathogens, transduce the signals via distinct intracellular pathways involving adaptor proteins such as MyD88 and Trif, and ultimately lead to inflammatory responses. Recent studies have suggested that TLRs may also play an important role in tissue injury due to non-infectious insults such as myocardial ischemia. Our goal is to determine the role of distinct TLR signaling pathways in the development of ischemic myocardial injury and the underlying mechanisms that control the effects.TLRs in Cardiac Dysfunction During Polymicrobial SepsisThere are 750,000 cases of sepsis each year. In severe cases such as septic shock, mortality reaches more than 40%. During sepsis, components of microorganisms interact with the host immune system and induce a profound systemic inflammatory response clinically manifested as hypotension, poor tissue perfusion, and organ dysfunction. Cardiac dysfunction represents a main feature of severe sepsis and contributes to its high mortality. Yet our understanding of the signaling mechanisms controlling this critical event remains incomplete. The goal of this project is to define the role of TLR signaling in the pathogenesis of sepsis. Using a mouse model of polymicrobial peritonitis sepsis and a variety of genetically-modified mouse strains, we test the contribution of a specific TLR signaling to the development of septic injury such as cardiac dysfunction and mortality. Various techniques have been established in the lab to measure myocardial dysfunction during sepsis, including serial echocardiography in vivo, isolated hearts perfused in a Langendorff system, and sarcomere shortening and intracellular Ca2+ transients in single cardiomyocytes.
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