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Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation

靶向免疫反应基因 1 (Irg1) 和衣康酸对移植供体心脏进行心脏保护

基本信息

批准号：
10895712
负责人：
Paul Tang
金额：
$ 67.09万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10895712
关键词：
Acetylation Alkylation Animals Anti-Inflammatory Agents Antiepileptic Agents Antioxidants Biology Cardiac Cardiac Myocytes Cardiac Output Cell Culture Techniques Cells Cessation of life Citric Acid Cycle Clinical Cre lox recombination system Cre-LoxP Cryopreservation Cysteine Data Dependovirus Endothelial Cells Enhancers Enzymes Epilepsy Erythroid Exposure to Family suidae Future Genes Geography Goals HDAC4 gene Heart Heart Injuries Heart Transplantation Heart failure Histidine Histone Deacetylase Inhibitor Histones Hour Human Immune Immune Targeting Incidence Inflammation Mediators Ischemia Kidney Kidney Failure Knock-out Knowledge Liver Mediating Medical Medical center Messenger RNA Mitochondria Modeling Modification Mus Mutate Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Organ Outcome Output Pathway interactions Patients Perfusion Perioperative Pharmaceutical Preparations Play Proteins Refractory Reperfusion Injury Reperfusion Therapy Research Resources Risk Role Site Stroke Succinates Tamoxifen Techniques Therapeutic Time Transgenic Mice Translations Transplant Recipients Transplantation Treatment Failure Tryptophan United States Food and Drug Administration Up-Regulation Valproic Acid Waiting Lists cardioprotection cell type chromatin immunoprecipitation druggable target efficacy evaluation ex vivo perfusion graft dysfunction heart function heart preservation heme oxygenase-1 immunoregulation improved inducible Cre liver injury mouse model novel novel therapeutic intervention organ allocation overexpression pre-clinical preservation programs protective effect side effect single-cell RNA sequencing superoxide dismutase 1 therapy development transcription factor transplant model

项目摘要

Heart transplantation is considered gold standard therapy for end-stage heart failure. However, demand currently far outstrips supply due to multiple challenges. An important limitation is the occurrence of primary graft dysfunction (PDG) in 10-20% of patients and contributes greatly to adverse clinical outcomes and resource utilization. PGD occurs when donor heart function and output is inadequate end organ perfusion. Risk for significant PDG increases when donor heart preservation time is greater than 4 hours. Valproic acid (VPA), a histone deacetylase inhibitor, is a “Food and Drug Administration (FDA)” approved drug traditionally used for the treatment of epilepsy. We now convincingly demonstrate that addition of VPA can dramatically improve donor heart function and improve ischemic tolerance compared to preservation using Histidine-Tryptophan- Ketoglutarate (HTK) preservation solution alone. This was seen in murine heart reperfusion models in the setting of ex-vivo perfusion and transplantation. Furthermore, we show evidence that VPA achieves this by upregulating tricarboxylic acid cycle enzyme Irg1 which produces the anti-inflammatory metabolite “itaconate”. Indeed, our cardiac reperfusion model confirms the impressive upregulation of Irg1 above baseline driven by VPA treatment, and this was accompanied by robust activation of antioxidant pathway mechanisms through Nrf2 transcription factor. Chromatin immunoprecipitation showed that VPA treatment increased Irg1 enhancer activity as indicated by increased occupancy by acetylated H3K27 histone. Importantly, VPA treatment of stored human donor hearts also upregulated Irg1 expression and decreased the expression of inflammatory mediators suggesting translational relevance for large animal and human clinical settings. For this proposal, we plan to: (1) Identify the cell type through which Irg1 acts and we hypothesize that it is most likely through cardiomyocytes (CM) and endothelial cells (EC). The is achieved using transgenic mice with conditional deficiency of Irg1 in these cell types using inducible Cre-Lox technology. We will also examine overexpression models using adeno-associated virus mediated expression Irg1 mRNA. (2) Using cell culture, we will determine whether Irg1/itaconate mediated alkylation modifications on Nrf2 pathway antioxidant proteins impacts their function. We will treat cells with itaconate and then identify as well as mutate relevant alkylation modifications sites at the cysteine residue of antioxidant proteins to determine their importance. (3) We will determine the efficacy of VPA for improving donor heart function and ischemic tolerance in pigs and humans. We will also corroborate mechanisms of VPA mediated cardioprotection identified in murine models. This project has critical clinical implications such as decreasing the PGD incidence, allow transport of donor hearts over longer distances to facilitate organ allocation, and improve clinical transplantation outcomes. Reduction in perioperative donor heart injury by harnessing the cardioprotective effect of VPA and Irg1/itaconate is novel and potentially relevant for preservation of other organs such as the livers and kidneys.

心脏移植被认为是终末期心力衰竭的金标准治疗方法。然而,需求