Kidney-Lung interactions during ischemia-reperfusion injury

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): [unreadable] This mentored clinical scientist research Career Development Award (KO8) proposal describes the 5-year[unreadable] training program for Dr. Heitham Hassoun. The proposal builds upon the candidate's strengths and prior[unreadable] research skills, and takes advantage of the extensive resources available at The Johns Hopkins University.[unreadable] Through the mentorship of Drs. Hamid Rabb and Rubin Tuder, and a structered didactic program, Dr.[unreadable] Hassoun will be given the tools and training to advance to the level of a fully independent surgeon scientist.[unreadable] The overall objective of this research proposal is to gain an understanding of the pathophysiological[unreadable] kidney-lung interactions during kidney ischemia-reperfusion injury (IRI) with an emphasis on the pulmonary[unreadable] endothelial response under these conditions. Despite advances in renal replacement therapy, acute kidney[unreadable] injury (AKI) continues to be associated with unacceptably high mortality. Recent studies have shown the[unreadable] importance of AKI on dysfunction of extra-renal organs, and with current availability of dialysis, AKIassociated[unreadable] distant organ injury constitutes the major cause of death in these patients. Based on prior clinical[unreadable] and laboratory investigations, we hypothesize that kidney IRI induces T lymphocyte dependent pulmonary[unreadable] endothelial apoptosis that contributes to subsequent acute lung injury (All).[unreadable] Specific aim #1 will characterize the effect of kidney IRI on acute lung injury and inflammation. Using[unreadable] established rodent models of ischemic AKI, we will investigate the in vivo effects of kidney IRI on lung injury[unreadable] and inflammation and the in vitro effects of post-IRI plasma on cultured endothelial barrier function.[unreadable] Specific aim #2 will investigate the role of pulmonary apoptosis in ischemic AKI-induced ALL Specifically,[unreadable] we will determine if pulmonary endothelial apoptosis mediates 1) kidney IRI-induced All in vivo and 2) post-[unreadable] IRI plasma induced barrier dysfunction in vitro, and identify the potential death receptor pathways involved.[unreadable] Specific aim #3 will investigate the potential role of T lymphocyte mediated pathways on kidney IRIinduced[unreadable] pulmonary apoptosis and ALL Using mice deficient in T cells/T cell subsets as well as adoptive[unreadable] transfer techniques, we will determine if T cells mediate pulmonary apoptosis and ALL[unreadable] The findings of the proposed studies will provide insight into the effector mechanisms of kidney-lung[unreadable] interactions during ischemia-reperfusion injury and serve as the basis for further mechanistic studies. [unreadable]