HDAC2 Inhibition Mitigates Renal Ischemia Reperfusion Injury

HDAC2 抑制可减轻肾缺血再灌注损伤

基本信息

批准号：
9754112
负责人：
Matthew Howard Levine
金额：
$ 36.29万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754112
关键词：
Acetylation Acetyltransferase Affect Allografting Animals Biochemical Biological Assay Blood Vessels Cardiopulmonary Bypass Cell Line Cessation of life ChIP-seq Charge Chromatin Chromosomes Clinical Comorbidity Complex DNA DNA Binding Data Deacetylase Development Dominant-Negative Mutation Donor person Epithelial Cells Epithelium Fibrosis Functional disorder Future Gene Activation Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Transcription Goals Graft Survival HDAC1 gene HDAC2 gene Health system Heart Arrest Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Image Immunosuppression Impairment Injury Interruption Ischemia KDM1A gene Kidney Kidney Transplantation Knock-out Knockout Mice Magnetic Resonance Imaging Mediating Medical Metabolic Metabolism Modeling Molecular Molecular Conformation Morbidity - disease rate Mus NuRD complex Nuclear Nuclear Protein Nuclear Proteins Operative Surgical Procedures Organ Organ Donor Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Site Play Process Protein Family Protein Isoforms Proteins Renal function Reperfusion Injury Role Series Site Source Specificity Standardization Structure System Tail Techniques Testing Time Tissues Translating Translations Transplant Recipients Transplantation Trauma Tubular formation Vascular blood supply Work base clinical application clinically relevant cost functional disability genetic manipulation genetic regulatory protein graft function improved in vivo inhibitor/antagonist injury prevention innovation interest member metabolic imaging mortality mutant non-histone protein novel novel strategies preservation promoter protective effect protein complex protein expression renal ischemia transplant model

项目摘要

Project Summary Renal ischemia reperfusion injury (IRI) is a major source of medical morbidity and mortality, affecting diverse medical scenarios including transplantation, cardiac arrest, cardiopulmonary bypass, trauma, and vascular surgery. Despite the use of preservation solution and minimization of organ ischemia time, early allograft dysfunction occurs in at least 30% of deceased donor transplant recipients and this number is rising with the enhanced use of marginal organ donors. Impaired early graft function impacts long term graft performance and graft loss is a predictor of death. Despite significant efforts, no specific therapies to mitigate ischemic injury have reached clinical use. We have identified that inhibition of histone/protein deacetylases (HDACs), a family of proteins that remove acetyl groups from DNA-associated histone proteins as well as other groups of proteins, is effective in mitigating early renal functional impairment and the development of fibrosis after renal IRI. We have narrowed the specificity of this beneficial effect to the nuclear class I HDACs which tightly regulate broad patterns of gene expression. We have subsequently identified that HDAC2 deletion, even when confined to the kidney itself, conveys major protection from ischemia reperfusion injury. Conversely, deletion of closely homologous HDAC1 leads to impaired renal IRI tolerance. We thus propose to identify the mechanism behind the HDAC2 deletion effect with the intent of translating this benefit to clinically relevant scenarios of renal ischemia such as transplantation and cardiopulmonary bypass. Our proposal uses whole animal, cellular, and molecular approaches to define the role that class I HDACs play in renal ischemia tolerance. We will define remaining unanswered questions such as tissue specificity of effects in cold ischemia transplant models, understand tissue specificity by confining HDAC deletion to renal tubular epithelium, and use innovative hyperpolarized 13C MRI to identify if HDACs are altering in vivo metabolism. We will then use cellular approaches to assess whether inhibiting the deacetylase function of HDAC2 can reproduce the deletion effects, with the possibility of focusing translational targets on deacetylase inhibitors. Lastly, we will utilize molecular approaches to identify the impact that HDAC2 deletion has on nuclear corepressor complex formation, localization, and DNA binding, further highlighting possible mechanisms for future translation. Our studies intend to translate a highly novel finding of a single HDAC knockout drastically improving in vivo renal ischemia tolerance to a clinically approachable process by better understanding how the in vivo effects are achieved. This may have major impact on the development of strategies to minimize renal ischemic damage, which is a major source of cost and comorbidity in our health system.

项目概要肾缺血再灌注损伤（IRI）是医疗发病率和死亡率的一个主要来源，影响着多种疾病医疗场景包括移植、心脏骤停、体外循环、创伤和血管外科手术。尽管使用保存液并最大限度地减少器官缺血时间，早期同种异体移植至少 30% 的已故供体移植受者出现功能障碍，并且这一数字随着加强边缘器官捐献者的利用。早期移植物功能受损会影响长期移植物性能移植物丢失是死亡的预测因子。尽管付出了巨大的努力，但没有减轻缺血的具体疗法损伤已达到临床使用。我们已经发现，组蛋白/蛋白脱乙酰酶 (HDAC) 的抑制是一种从 DNA 相关组蛋白以及其他组蛋白中去除乙酰基的蛋白质家族蛋白质，可有效减轻早期肾功能损伤和肾衰竭后纤维化的发展 IRI。我们已经将这种有益作用的特异性缩小到核 I 类 HDAC，它紧密地调节基因表达的广泛模式。我们随后发现 HDAC2 缺失，即使仅限于肾脏本身，对缺血再灌注损伤具有重要的保护作用。反之，删除密切同源的 HDAC1 的缺失会导致肾 IRI 耐受性受损。因此，我们建议确定 HDAC2 缺失效应背后的机制，旨在将此益处转化为临床相关的肾缺血的情况，例如移植和体外循环。我们的建议使用整体动物、细胞和分子方法来定义 I 类 HDAC 在肾缺血中的作用宽容。我们将定义尚未解答的问题，例如冷缺血效应的组织特异性移植模型，通过将 HDAC 删除限制在肾小管上皮来了解组织特异性，以及使用创新的超极化 13C MRI 来确定 HDAC 是否正在改变体内代谢。然后我们将使用细胞方法来评估抑制 HDAC2 的脱乙酰酶功能是否可以重现缺失效应，有可能将翻译靶点集中在脱乙酰酶抑制剂上。最后，我们将利用分子方法确定 HDAC2 缺失对核辅阻遏物复合体的影响形成、定位和 DNA 结合，进一步强调了未来翻译的可能机制。我们的研究旨在转化单 HDAC 敲除显着改善体内肾功能的高度新颖的发现通过更好地了解体内效应，对临床上可行的过程进行缺血耐受实现了。这可能对最大限度地减少肾缺血损伤的策略的制定产生重大影响，这是我们卫生系统成本和合并症的主要来源。