Histone/Protein Deacetylase Inhibitors Minimize Renal Ischemia-Reperfusion Injury

组蛋白/蛋白脱乙酰酶抑制剂可最大限度地减少肾缺血再灌注损伤

基本信息

批准号：
8661174
负责人：
Matthew Howard Levine
金额：
$ 15.32万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661174
关键词：
Abbreviations Acute Kidney Tubular Necrosis Address Allografting Applications Grants Area Award Binding Biochemical Biochemistry Biological Biology Blood Urea Nitrogen Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular Surgical Procedures Cells Cerebral Ischemia Chemicals Clinical Complex Cytoplasm Data Deacetylase Deacetylation Development Disease Environment Epigenetic Process Epithelial Family Functional disorder Goals Heat shock proteins Heat-Shock Response Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Immunologic Memory Immunology Impairment Individual Inflammation Inflammatory Inflammatory Response Institutes Investigation Kidney Kidney Transplantation Knockout Mice Knowledge Laboratories Lead Life Mentored Clinical Scientist Development Award (K08)Mentors Mentorship Mesenchymal Methods Mission Modeling Mus Myocardial Infarction Operative Surgical Procedures Organ Organ Donor Organ Transplantation Outcome Patients Pediatric Hospitals Pennsylvania Performance Perfusion Philadelphia Physiological Processes Play Polymerase Chain Reaction Process Proteins Regulatory T-Lymphocyte Renal function Reperfusion Injury Research Research Project Grants Research Proposals Research Training Role Scientist Signal Pathway Signal Transduction Site Specificity Stroke T-Lymphocyte Therapeutic Therapeutic Agents Tissues Transcriptional Regulation Transplant Recipients Transplant Surgeon Transplantation Transplantation Immunology Trichostatin A Universities University Hospitals Ursidae Family Vorinostat Warm Ischemia Work base career career development clinical practice clinically relevant histone acetyltransferase improved inhibitor/antagonist innovation insight knowledge base member molecular array novel prevent renal ischemia response response to injury restoration small molecule stem success

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本指导临床科学家发展奖（K08）申请提议对通过操纵组蛋白脱乙酰酶（HDAC）功能来改善小鼠肾脏模型中的缺血再灌注损伤（IRI）进行彻底研究。该提案将通过促进申请人的知识库扩展到需要这些新领域指导的新颖探究领域来实现发展奖的教育目标。协助这项拨款提案的免疫学、应用表观遗传学、生物化学和移植方面的导师的专业知识对于成功完成该奖项的教育使命以及跨越这些不同领域的拟议研究计划的执行至关重要。缺血再灌注损伤仍然是器官移植成功利用的主要障碍，并且在心血管疾病和中风等其他领域具有重要的临床意义。大量的努力集中在开发减轻 IRI 的方法上，但迄今为止几乎没有取得成功。根据我们的初步数据，我们假设 HDAC 的表观遗传操作可以显着减轻 IRI。由于小分子 HDAC 抑制剂 (HDACi) 是可用的，并且事实上有些已被批准用于临床，我们认为 HDAC 抑制将提供一种有前途的方法，可能在 IRI 导致终末器官的各种疾病过程中具有临床意义。损坏或功能障碍。具体来说，拟议的工作将：1）研究 HDAC 抑制在小鼠肾脏模型中减轻 IRI 中的作用，2）定义其抑制作用负责减轻 IRI 的特定类别或个体 HDAC 成员，以及 3）确定限制是否通过 HDAC 抑制对 IRI 的影响是通过调节肾实质本身的 IRI 耐受性、调节免疫反应和炎症造成的继发性损伤，或两者兼而有之。这项拟议的工作具有创新性，因为它系统地研究了 IRI 领域的表观遗传操作应用。过去已经系统地完成了这项工作，但 HDAC 抑制在 IRI 中的真正作用位点尚未确定。这种方法此前尚未用于 IRI 肾脏模型。汇集该应用导师的专业知识，可以接触到生化抑制剂、缺乏特定 HDAC 的小鼠，以及成功完成这项工作所必需的免疫学和移植专业知识。从这项拟议工作中获得的知识与对 IRI 的组织和炎症反应的基本科学理解直接相关，并且有可能直接影响器官移植、心脏和血管手术以及心肌梗死和治疗等多种临床领域。中风。如果被证明有效，小分子 HDAC 抑制剂在减轻上述临床情况下的 IRI 方面具有巨大的前景。