Metabolic Rewiring of the Heart Through Reductive Carboxylation

通过还原羧化重塑心脏的代谢

基本信息

批准号：
10617325
负责人：
Anja Karlstaedt
金额：
$ 24.9万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10617325
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylation Acute Myelocytic Leukemia Address Adult Amino Acids Atrophic Autophagocytosis Branched-Chain Amino Acids Cancer Survivor Cardiac Myocytes Cardiotoxicity Cardiovascular Diseases Cause of Death ChIP-seq Chemistry Chronic Citrates Citric Acid Cycle Cytosol Cytostatics Data Decarboxylation Development Dilated Cardiomyopathy Energy Metabolism Epigenetic Process Experimental Models Functional disorder Future Gene Expression Genetic Glucose Glutamine Goals Heart Heart failure Histones Impairment Isocitrate Dehydrogenase Isocitrates Ketoglutarate Dehydrogenase Complex Label Lead Link Lysine Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator Mentors Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Methylation Mitochondria Modeling Modification Mus Muscle Cells Mutate Mutation Myocardial dysfunction Myocardium NADH NADP Oxidation-Reduction Oxidoreductase Pathogenesis Pathologic Pathway interactions Patients Phase Process Production Protein Biosynthesis Protein Isoforms Proteome Proteomics Research Research Personnel Risk Role Stress Survivors Testing Tracer Training Tumor Biology Work alpha ketoglutarate amino acid metabolism cancer cell carboxylate carboxylation chemotherapeutic agent chemotherapy disability experimental study heart function heart metabolism high risk insight leukemia mathematical model mutant novel therapeutic intervention oxidation pharmacologic response self-renewal skeletal muscle wasting skills transcriptome sequencing tumor tumor metabolism tumorigenesis

项目摘要

Summary The term “cancer and the heart” traditionally refers to the cardiotoxic effects of chemotherapeutic agents. However, independent of any cytostatic treatment, cancer survivors have a five-fold higher risk for developing heart failure. Therefore, new therapeutic strategies must consider tumor biology when aiming at protecting the heart. For example, it has been observed that in isocitrate dehydrogenase (IDH) 1 and 2 mutant tumors, the elevated production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with systemic effects, including dilated cardiomyopathy. About 20% of acute myeloid leukemia cases harbor mutations of the IDH. These mutations lead to significantly reduced patient survival and cause metabolic dysfunction which are associated with high levels of the oncometabolite D2-HG. However, the extent to which D2-HG can directly impair cardiac function and metabolism, and which processes are involved, is still unknown. Recently I discovered that D2-HG mediates cardiac dysfunction by inhibiting α-ketoglutarate dehydrogenase, which leads to redirection of Krebs cycle intermediates, increased ATP citrate lyase activity, and increased histone 3 pan- acetylation. Furthermore, chronic treatment with D2-HG causes heart and skeletal muscle atrophy, suggesting that IDH mutation also stimulates structural remodeling. I now propose that inhibition of α-KG dehydrogenase by the oncometabolite D2-HG induces reductive carboxylation of α-KG in the heart resulting in pathologic structural remodeling. My goal is to determine the role of oncometabolism in the pathogenesis of heart failure. In the K99 phase, Specific Aim 1 will define the role of reductive carboxylation as a mediator for metabolic remodeling of the heart using the oncometabolite D2-HG as a model. Specific Aim 2 will define the role of reductive citrate metabolism as a link between energy substrate metabolism and epigenetic remodeling by lysine acetylation. These experiments will transition into the R00 phase, which in Specific Aim 3 will extend the findings to address the impact of branched chain amino acid metabolism and autophagy on proteomic remodeling in the metabolically deregulated state of D2-HG. Collectively, this project will advance the hypothesis that oncometabolic stress drives development of heart failure. These new insights ultimately change the way cancer and heart failure patients are treated.

概括 “癌症与心脏”一词传统上是指化疗药物的心脏毒性作用。然而，独立于任何细胞抑制剂治疗，癌症幸存者发生癌症的风险高出五倍因此，新的治疗策略在旨在保护心力衰竭时必须考虑肿瘤生物学。例如，已观察到在异柠檬酸脱氢酶 (IDH) 1 和 2 突变肿瘤中，致癌代谢物 D-2-羟基戊二酸 (D2-HG) 的产生增加与全身效应相关，包括扩张型心肌病，约 20% 的急性髓系白血病病例存在 IDH 突变。这些突变导致患者生存率显着降低并导致代谢功能障碍与高水平的致癌代谢物 D2-HG 有关，但是 D2-HG 可以直接影响的程度。损害心脏功能和新陈代谢，以及涉及哪些过程，目前尚不清楚。发现 D2-HG 通过抑制 α-酮戊二酸脱氢酶介导心脏功能障碍，从而导致重定向克雷布斯循环中间体，增加 ATP 柠檬酸裂解酶活性，并增加组蛋白 3 pan- 此外，长期使用 D2-HG 治疗会导致心脏和骨骼肌萎缩，这表明 IDH 突变也会刺激结构重塑，我现在提出抑制 α-KG。致癌代谢物 D2-HG 的脱氢酶诱导心脏中 α-KG 的还原羧化导致病理结构重塑我的目标是确定肿瘤代谢在肿瘤代谢中的作用。在 K99 阶段，具体目标 1 将定义还原羧化的作用。作为心脏代谢重塑的介质，使用致癌代谢物 D2-HG 作为模型。目标 2 将定义还原性柠檬酸代谢作为能量底物代谢和代谢之间的联系的作用。通过赖氨酸乙酰化进行表观遗传重塑，这些实验将过渡到 R00 阶段。具体目标 3 将扩展研究结果以解决支链氨基酸代谢和总的来说，该项目在 D2-HG 代谢失调状态下自噬对蛋白质组重塑的影响。这些新见解将推进肿瘤代谢应激导致心力衰竭发展的假设。最终改变癌症和心力衰竭患者的治疗方式。