Metabolic Control of Epigenetic Reprogramming in Neovascularization

新血管形成中表观遗传重编程的代谢控制

• 批准号: 10605418
• 负责人: Alexander J. Lu
• 金额: $ 3.68万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605418
• 关键词: Acetyl Coenzyme A; Affect; Attenuated; Biological Process; Blood Vessels; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cell Fate Control; Cell Line; Cells; Coin; DNA; Data; Disease; Endothelial Cells; Enzymes; Epigenetic Process; Fibroblasts; Gene Expression; Genetic; Global Change; Goals; Heart failure; Hindlimb; Histone Acetylation; Immune signaling; In Vitro; Inflammatory; Intervention; Ischemia; Knockout Mice; Laboratories; Link; Medicine; Metabolic; Metabolic Control; Metabolism; Mission; Modeling; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nuclear; Nutrient; Pathway interactions; Perfusion; Phenotype; Population; Post-Translational Protein Processing; Primary Cell Cultures; Process; Proteomics; Recovery; Regenerative Medicine; Reporter; Research Training; Role; Signal Pathway; Site; Syndrome; Testing; Tissues; Treatment Efficacy; Uridine Diphosphate N-Acetylglucosamine; candidate identification; established cell line; experimental study; fluidity; improved; in vivo; ischemic injury; limb ischemia; multiple omics; neovascularization; new therapeutic target; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; regenerative; regenerative approach; resilience; therapeutic angiogenesis; transdifferentiation; vasculogenesis

Project Summary The ability to restore the microvasculature and improve perfusion, by expanding the population of endothelial cells in vivo, would be a major advancement in cardiovascular medicine and create a novel therapeutic approach to cardiovascular disease. The proposed studies, aimed at identifying the role of O-GlcNAcylation in transdifferentiation and epigenetic plasticity, may reveal a novel mechanism of neovascularization and uncover new avenues for therapeutic angiogenesis and vasculogenesis (Carmeliet, 2005, Isner 1999). Activation of inflammatory signaling pathways is required to drive fibroblasts to undergo angiogenic transdifferentiation and become endothelial cells in vitro (Sayed, 2015). This process requires cell autonomous innate immune signaling, which triggers global changes in expression and activity of epigenetic modifiers (Lee, 2012). The term “transflammation” describes the process by which innate immune signaling promotes epigenetic plasticity and phenotypic fluidity. Recently, it has been shown that a glycolytic shift contributes to transdifferentiation by increased nuclear acetyl-CoA for histone acetylation (Lai, 2019). Although this glycolytic switch links metabolism to epigenetic modelling, the contribution of other metabolites to epigenetic plasticity in neovascularization remains unexplored. Preliminary data indicate that O-GlcNAcylation, and nutrient driven post-translational modification (PTM), is significantly elevated in angiogenic transdifferentiation and neovascularization following hindlimb ischemia. This observation raises the exciting possibility that O-GlcNAcylation links cell fate plasticity to metabolism in vascular transdifferentiation, and that targeting this PTM may be a new therapeutic avenue in regenerative medicine. The overarching hypothesis is that O-GlcNAcylation enhances neovascularization in recovery from ischemic injury by facilitating cell fate plasticity, and that perturbations to O-GlcNAcylation through genetic and pharmacologic manipulation will attenuate transdifferentiation and diminish neovascularization. The immediate goal will be to determine if O-GlcNAcylation is required for angiogenic transdifferentiation and to identify targets of O-GlcNAcylation contributing to epigenetic plasticity and cell fate fluidity in vascular transdifferentiation and neovascularization. The proposed studies on O-GlcNAcylation in transdifferentiation will identify an epigenetic mechanism for cellular plasticity and a novel therapeutic target to enhance endogenous neovascularization for treatment of cardiovascular disease. The long term goal is to evaluate the therapeutic efficacy of targeting O-GlcNAcylation to enhance vascular recovery in non-ischemic and ischemic models of cardiovascular disease, such as heart failure and myocardial infarction. Aim 1: Determine the role of O-GlcNAcylation in transdifferentiation and DNA accessibility in vitro. Aim 2: Determine the role of O-GlcNAcylation in transdifferentiation and neovascularization in vivo.

项目摘要 通过扩大内皮细胞群来恢复微血管和改善灌注的能力 细胞，将是心血管医学的重大进步，并创造一种新的治疗方法， to cardiovascular心血管disease疾病.所提出的研究旨在确定O-GlcNAc化在 转分化和表观遗传可塑性，可能揭示新血管形成的新机制，并揭示 治疗性血管生成和血管发生的新途径（Carmeliet，2005，Isner 1999）。 炎症信号通路的激活是驱动成纤维细胞进行血管生成所必需的。 在体外转分化并成为内皮细胞（Sayed，2015）。这个过程需要细胞自主 先天免疫信号传导，其触发表观遗传修饰物的表达和活性的整体变化（Lee， 2012年）。术语“transflammation”描述了先天免疫信号传导促进免疫应答的过程。 表观遗传可塑性和表型流动性。最近，已经表明糖酵解转变有助于 通过增加用于组蛋白乙酰化的核乙酰辅酶A进行转分化（Lai，2019）。 虽然这种糖酵解开关将代谢与表观遗传模型联系起来，但其他代谢物对糖酵解的贡献并不明显。 新血管形成的表观遗传可塑性仍然未被探索。初步数据表明，O-GlcNAc酰化， 和营养驱动的翻译后修饰（PTM），在血管生成中显著升高， 转分化和新血管形成。这一观察提出了令人兴奋的 O-GlcNAc酰化可能将细胞命运可塑性与血管转分化中的代谢联系起来， 靶向这种PTM可能是再生医学的一种新的治疗途径。 最重要的假设是，O-GlcNAc酰化在缺血性心脏病恢复过程中促进新血管形成。 通过促进细胞命运可塑性损伤，以及通过遗传和 药理学操作将减弱转分化并减少新血管形成。立即 我们的目标是确定O-GlcNAc酰化是否是血管生成转分化所必需的，并确定靶点 O-GlcNAc化有助于血管转分化中的表观遗传可塑性和细胞命运流动性， 新生血管形成对转分化中O-GlcNAc化的拟议研究将确定一种新的转分化途径。 细胞可塑性的表观遗传机制和增强内源性 用于治疗心血管疾病的新血管形成。长期目标是评估 靶向O-GlcNAc化以增强非缺血性和缺血性患者血管恢复的治疗功效 心血管疾病模型，如心力衰竭和心肌梗死。 目的1：研究O-GlcNAcylation在体外转分化和DNA可及性中的作用。 目的2：研究O-GlcNAc化在转分化和新生血管形成中的作用。