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Acetate and Endothelial Pathobiology

醋酸盐和内皮病理学

基本信息

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
项目类别：
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

项目摘要

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