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

基本信息

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
项目类别：
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

项目摘要

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种群来恢复微脉管系统并改善灌注的能力体内细胞将是心血管医学的主要进步，并创建一种新型的治疗方法患心血管疾病。拟议的研究旨在确定O-Glcnacylation在转变和表观遗传可塑性可能揭示了新型的新生血管形成机制，并发现了治疗性血管生成和血管生成的新途径（Carmeliet，2005，Isner 1999）。需要激活炎症信号通路才能驱动成纤维细胞进行血管生成转分化并在体外变成内皮细胞（Sayed，2015年）。此过程需要单元自动先天免疫信号传导，它触发了表观遗传修饰剂的全球表达和活性变化（Lee， 2012）。 “转炎”一词描述了先天免疫信号促进的过程表观可塑性和表型流动性。最近，已经表明糖酵解转移有助于组蛋白乙酰基的核乙酰辅酶A的转变（LAI，2019）。尽管这种糖酵解开关将代谢与表观遗传建模联系起来，但其他代谢物对新血管形成中的表观可塑性仍然出乎意料。初步数据表明O-Glcnacylation，养分驱动后翻译后修饰（PTM）在血管生成中显着升高后肢缺血后的转变和新血管化。这个观察使令人兴奋的 O-Glcnacylation将细胞脂肪可塑性与血管转分化的代谢联系起来的可能性，并且瞄准该PTM可能是再生医学中的新治疗大道。总体假设是O-Glcnacylation增强了缺血性恢复中的新血管通过促进细胞命运可塑性的伤害，以及通过遗传和药理学操纵将减轻转分化并减少新血管形成。直接目标是确定血管生成转分化是否需要O-Glcnacylation并识别靶标 O-Glcnacylation在血管转分化和新血管形成。拟议的关于转分化的O-Glcnacylation的研究将确定细胞塑性的表观遗传机制和一种新型的热靶标，以增强内源性用于治疗心血管疾病的新血管化。长期目标是评估靶向O-Glcnacylation的治疗效率，以增强非缺血性和缺血性的血管恢复心血管疾病的模型，例如心力衰竭和心肌梗塞。 AIM 1：确定O-Glcnacylation在体外跨分化和DNA可及性中的作用。 AIM 2：确定O-Glcnacylation在体内转分化和新血管化中的作用。