Acetate and Endothelial Pathobiology

醋酸盐和内皮病理学

• 批准号: 10736268
• 负责人: Zoltan P Arany
• 金额: $ 74.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736268
• 关键词: Acetates; Acetyl Coenzyme A; Acetylation; Animal Model; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Bypass; Cellular Metabolic Process; Chronic; Citrates; Cytoplasm; Data; Development; Disease; Endothelial Cells; Endothelium; Enzymes; Event; Feedback; Generations; Genetically Engineered Mouse; Glucose; Goals; Hypoxia; In Vitro; Inflammation; Link; Mass Spectrum Analysis; Mesenchymal; Metabolic; Metabolic Activation; Metabolic Control; Metabolic Pathway; Metabolism; Mitochondria; Mus; Myocardial Infarction; Oral; Paint; Pathology; Pathway interactions; Peripheral Vascular Diseases; Phosphorylation; Physiological; Play; Prevention; Process; Production; Protein Acetylation; Pulmonary Hypertension; Pyruvate; Pyruvate Dehydrogenase Complex; RNA Interference; Regulation; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Source; Stroke; Techniques; Testing; Therapeutic; Therapeutic Agents; Transforming Growth Factor beta; Translating; Transplantation; anaerobic glycolysis; clinical practice; defined contribution; driving force; efficacy testing; in vitro testing; in vivo; in vivo evaluation; inhibitor; mouse model; nanoparticle; nanoparticle delivery; novel; novel therapeutic intervention; novel therapeutics; prevent; pulmonary arterial hypertension; pyruvate dehydrogenase; side effect; success; targeted treatment; therapeutic evaluation; therapeutic target; therapeutically effective; translational approach; vascular inflammation

Chronic vascular inflammation is a hallmark of atherosclerosis, pulmonary arterial hypertension (PAH) and related conditions. It is also one of the principal causes of endothelial- to-mesenchymal transition (EndMT). We have recently demonstrated that disruption of EndMT, achieved by inhibiting endothelial-specific TGFβ signaling input, results in extensive (~70%) regression of established atherosclerotic lesion and prevention of development of new ones. It also prevents development of hypoxia-induced PAH. These data suggest that EndMT is key to the development and progression of illnesses associated with chronic inflammation, such as atherosclerosis, PAH, and transplant arteriopathy. However, a therapeutic strategy that relies on suppressing EndMT via control of endothelial TGFβ signaling is complicated because of the need of endothelial-specific delivery of therapeutic agents (systemic inhibition of TGFβ signaling is fraught with side effects and has been shown to promote atherosclerosis via its effects on smooth muscle cells). For these reasons, we focused on identifying another EndMT control point that can serve as an effective therapeutic target. Since endothelial cells have unique metabolic requirements and pathways, we concentrated on identifying potential metabolic-related control of EndMT. Our preliminary studies indicate that there indeed is metabolic control of EndMT that operates via acetylation-dependent regulation of TGFβ signaling. Moreover, the Ac-CoA needed for these acetylation events appears to be in large part derived atypically from acetate. Our goal in this application is to rigorously define and characterize the unique endothelial metabolic pathway that leads to generation of cytoplasmic Ac-CoA from acetate and the role that this Ac- CoA plays in TGFβ signaling. This will be tested in vitro and in vivo using genetically engineered mice. Finally, we will test two distinct translational strategies – a nanoparticle-based EC-specific RNAi delivery, and an oral specific inhibitor to test the effect of suppression of acetate-based Ac-CoA production on the development and progression of atherosclerosis

慢性血管炎症是动脉粥样硬化、肺动脉粥样硬化的标志 高血压（PAH）和相关疾病。这也是内皮细胞异常的主要原因之一 间质转化（EndMT）。我们最近证明了 EndMT 的破坏， 通过抑制内皮特异性 TGFβ 信号输入来实现，导致广泛 (~70%) 消退已形成的动脉粥样硬化病变并预防新病变的发展。它 还可以预防缺氧引起的 PAH 的发生。这些数据表明 EndMT 是关键 与慢性炎症相关的疾病的发生和进展，例如 动脉粥样硬化、PAH 和移植动脉病。 然而，依赖于通过控制内皮细胞抑制 EndMT 的治疗策略 TGFβ 信号传导非常复杂，因为需要内皮特异性传递 治疗药物（系统性抑制 TGFβ 信号传导充满副作用，并且 已被证明可通过其对平滑肌细胞的作用促进动脉粥样硬化）。对于这些 原因，我们专注于确定另一个 EndMT 控制点，可以作为有效的 治疗目标。由于内皮细胞具有独特的代谢需求和途径， 我们专注于识别 EndMT 潜在的代谢相关控制。 我们的初步研究表明，EndMT 确实存在代谢控制 通过 TGFβ 信号传导的乙酰化依赖性调节发挥作用。此外，Ac-CoA 需要 因为这些乙酰化事件似乎很大程度上非典型地源自乙酸盐。我们的目标 在这个应用中的目的是严格定义和表征独特的内皮代谢 导致从乙酸盐生成细胞质 Ac-CoA 的途径以及该 Ac-CoA 的作用 CoA 在 TGFβ 信号传导中发挥作用。这将使用基因工程进行体外和体内测试 老鼠。最后，我们将测试两种不同的转化策略——基于纳米粒子的 EC 特定策略 RNAi 递送和口服特异性抑制剂来测试醋酸盐抑制效果 Ac-CoA 的产生对动脉粥样硬化的发生和进展的影响