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的标志，即肺动脉 高血压(PAH)及相关情况。它也是内皮细胞的主要原因之一- 向间质转化(EndMT)。我们最近证明了EndMT的破坏， 通过抑制内皮细胞特异性转化生长因子β信号输入实现，结果广泛(~70%) 已建立的动脉粥样硬化病变的消退和防止新的病变的发展。它 还可以防止低氧诱导的PAH的发展。这些数据表明，EndMT是 慢性炎症与慢性炎症有关的疾病的发展和发展，例如 动脉粥样硬化、肺动脉高压和移植物动脉病。 然而，依赖于通过控制内皮抑制EndMT的治疗策略 转化生长因子β信号转导是复杂的，因为需要血管内皮细胞特异性递送 治疗药物(全身抑制转化生长因子β信号转导充满副作用 已被证明通过对平滑肌细胞的作用而促进动脉粥样硬化)。为了这些 原因，我们专注于确定另一个可以作为有效的EndMT控制点 治疗靶点。由于内皮细胞有独特的代谢要求和途径， 我们专注于确定EndMT的潜在代谢相关控制。 我们的初步研究表明，EndMT确实存在代谢控制，即 通过乙酰化依赖的方式调节转化生长因子β信号。此外，Ac-CoA需要 对于这些乙酰化事件，似乎在很大程度上非典型地来自醋酸盐。我们的目标 在这方面的应用是严格定义和表征独特的内皮代谢 由醋酸盐产生细胞质Ac-CoA的途径及其在细胞中的作用。 辅酶A在转化生长因子β信号转导中发挥作用。这将在体外和体内使用基因工程进行测试 老鼠。最后，我们将测试两种不同的翻译策略--基于纳米颗粒的EC特定策略 RNAi传递，并口服特异性抑制剂，以测试对醋酸基的抑制效果 AC-CoA的产生与动脉粥样硬化的发生发展