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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
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University of Pennsylvania
Schools of Medicine
United States
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Aufhauser Jr, David D; Sadot, Eran; Murken, Douglas R et al. (2018) Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy. Ann Surg 267:922-928
Angelin, Alessia; Gil-de-Gómez, Luis; Dahiya, Satinder et al. (2017) Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab 25:1282-1293.e7
Reese, Peter P; Harhay, Meera N; Abt, Peter L et al. (2016) New Solutions to Reduce Discard of Kidneys Donated for Transplantation. J Am Soc Nephrol 27:973-80
Akimova, Tatiana; Levine, Matthew H; Beier, Ulf H et al. (2016) Standardization, Evaluation, and Area-Under-Curve Analysis of Human and Murine Treg Suppressive Function. Methods Mol Biol 1371:43-78
Aufhauser Jr, David D; Wang, Zhonglin; Murken, Douglas R et al. (2016) Improved renal ischemia tolerance in females influences kidney transplantation outcomes. J Clin Invest 126:1968-77
Levine, Matthew H; Wang, Zhonglin; Xiao, Haiyan et al. (2016) Targeting Sirtuin-1 prolongs murine renal allograft survival and function. Kidney Int 89:1016-1026
Redfield, Robert R; Gupta, Meera; Rodriguez, Eduardo et al. (2015) Graft and patient survival outcomes of a third kidney transplant. Transplantation 99:416-23
Gupta, Meera; Wood, Alexander; Mitra, Nandita et al. (2015) Repeat Kidney Transplantation After Failed First Transplant in Childhood: Past Performance Informs Future Performance. Transplantation 99:1700-8
Levine, M H; Wang, Z; Bhatti, T R et al. (2015) Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation. Am J Transplant 15:965-73
Reese, Peter P; Shults, Justine; Bloom, Roy D et al. (2015) Functional status, time to transplantation, and survival benefit of kidney transplantation among wait-listed candidates. Am J Kidney Dis 66:837-45

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