This application for a Mentored Clinical Scientist Development Award (K08) proposes a thorough investigation into the improvement of ischemia reperfusion injury (IRI) in a mouse kidney model via manipulation of the function of histone deacetylases (HDACs). This proposal will fulfill the educational objective of the development award by facilitating the expansion of the applicant's knowledge base into novel lines of inquiry requiring mentorship in these new areas. The expertise of the mentors assisting in this grant proposal in immunology, applied epigenetics, biochemistry, and transplantation will be essential to the successful completion of both the educational mission of the award as well as the performance of the proposed research plan that spans these disparate areas. Ischemia reperfusion injury remains a major barrier to successful organ utilization in transplantation as well as bearing significant clinical relevance in other areas such as cardiovascular disease and stroke. A great deal of effort has focused on developing methods of mitigation of IRI but with little applicable success to date. Based on our preliminary data, we hypothesize that epigenetic manipulation of HDACs can mitigate IRI significantly. Since small molecule HDAC inhibitors (HDACi) are available and some, in fact, are approved for clinical use, we propose that HDAC inhibition will provide a promising approach that may bear clinical relevance in a variety of disease processes in which IRI leads to end organ damage or dysfunction. Specifically, the proposed work will: 1) investigate the role that HDAC inhibition plays in mitigating IRI in a murine kidney model, 2) define the specific class or individual HDAC member whose inhibition is responsible for mitigating IRI, and 3) determine if the limitation of IRI via HDAC inhibition is taking effect by modulating IRI tolerance of the renal parenchyma itself, by modulating the immune response and secondary damage inflicted by inflammation, or both. This proposed work is innovative, in that it systematically investigates applied epigenetic manipulation to the field IRI. This has been done systematically in the past and the true site of action of HDAC inhibition in IRI has not been defined. This approach has not been used in renal models of IRI previously. Bringing together the expertise of the mentors on this application gives access to the biochemical inhibitors, mice deficient in specific HDACs, and expertise in immunology and transplantation that will be necessary to complete this work successfully. The knowledge gained from this proposed work has direct relevance to both the basic scientific understanding of tissue and inflammatory responses to IRI as well as the potential to directly impact clinical fields as diverse as organ transplantation, cardiac and vascular surgery, and approaches to myocardial infarction and stroke. If proven effective, small molecule HDAC inhibitors have great promise in mitigating IRI in the clinical scenarios listed above.
This mentored research project describes an investigation of the role that histone deacetylase (HDAC) activity plays in responses to ischemia-reperfusion injury (IRI) and the potential benefit of HDAC manipulation in mitigating IRI. This work will utilize pan-HDAC, HDAC class, and individual HDAC small molecule inhibitors as well as mice genetically deficient in a variety of HDAC molecules to explore renal function after IRI in a murine renal ischemia model. Specifically, the proposed research will 1) define the HDAC class or individual HDAC molecule that participates in renal IRI, 2) determine the improvement in renal IRI tolerance that can be attained through selective and unselective HDAC inhibition, and 3) determine if the improvement in renal IRI tolerance brought about by HDAC inhibition acts on the renal parenchyma, the inflammatory response to IRI, or both. This knowledge has the potential to identify relevant targets for improving IRI responses that would have significant applicable benefit to human patients in organ transplantation, cardiac and cerebral ischemia, and cardiovascular surgery where IRI has significant clinical impact.
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