Regulation of Endothelial Lipid Metabolism in the Setting of Diabetes and Critical Limb Ischemia to Prevent Surgical Complications

糖尿病和严重肢体缺血时调节内皮脂质代谢以预防手术并发症

• 批准号: 10375540
• 负责人: Mohamed A. Zayed
• 金额: $ 52.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375540
• 关键词: Address; Adoption; Adult; Affect; Agonist; Amputation; Arterial Intimas; Arterial Occlusive Diseases; Atherosclerosis; Biochemical; Biochemical Process; Blood Vessels; Cardiac; Cell physiology; Choline; Chronic Disease; Clinical; Clinical Data; Clinical Management; Clinical Trials; Complement; Data; Diabetes Mellitus; Diet; Diffuse Pattern; Disease; Disease Progression; Endothelial Cells; Endothelium; Enzymes; Ethanolamines; Event; FASN gene; Fatty Acids; Fatty-acid synthase; Fenofibrate; Financial Hardship; Functional disorder; Future; Genes; Health; Homeostasis; Individual; Insulin Resistance; Intervention; Intervention Studies; Investigation; Isolated limb perfusion; Knock-out; Knowledge; Lead; Lipid Synthesis Pathway; Lipids; Low-Density Lipoproteins; Lower Extremity; Mediating; Membrane; Metabolic; Molecular; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Outcome; PPAR alpha; Patients; Peripheral; Peripheral arterial disease; Persons; Pharmaceutical Preparations; Pharmacology; Phospholipids; Phosphotransferases; Play; Post-Translational Protein Processing; Prevalence; Prevention strategy; Process; Protocols documentation; Reagent; Regulation; Research; Risk; Role; Serum; Signal Transduction; Smooth Muscle Myocytes; Surgical Management; Surgical complication; System; Techniques; Testing; Time; Tissues; Translations; Triglycerides; United States; base; burden of illness; cell type; conditional knockout; cost; critical limb Ischemia; diabetes pathogenesis; double-blind placebo controlled trial; effective therapy; high risk; improved; individualized medicine; innovation; insight; lipid biosynthesis; lipid metabolism; mouse model; novel; prevent; psychologic; targeted treatment; treatment strategy

PROJECT ABSTRACT Background & Significance: Peripheral arterial disease (PAD) affects 12 million people in the US (1 in 27 individuals). Individuals with diabetes are nearly 10 times more likely to develop end-stage surgical complications such as critical limb ischemia (CLI) and major lower extremity amputation. This leads to significant health, psychological, and financial burdens on surgical patients with diabetes. Therefore, it is paramount to better understand this chronic disease process in order to develop more effective treatment strategies, and improve the health of these patients. Fenofibrate, a peroxisome proliferator activated receptor alpha (PPARα) agonist that lowers serum triglycerides, is the only medication to date shown to reduce peripheral amputation rates in patients with diabetes. However, it is unknown how Fenofibrate confers this benefit, and therefore it is seldom used in the clinical management of surgical patients with diabetes and CLI who are at risk of amputation. De novo lipogenesis is a multi-step lipid synthesis pathway that is known to contribute to the pathogenesis of diabetes in non-vascular organ tissue, and is regulated by fatty acid synthase (FAS) and choline/ethanolamine phosphotransferase-1 (CEPT1). Interplay between these enzymes can lead to activation of PPARα-mediated signaling. It is unknown whether Fenofibrate can impact de novo lipogenesis, endothelial cell (EC) lipid metabolism, and peripheral arterial atheroprogression in the setting of diabetes. Preliminary Data: We observed that Fenofibrate can indeed affect peripheral limb perfusion in the setting of altered de novo lipogenesis. We also observed that both CEPT1 and FAS are abundant in the peripheral arterial intima of patients with diabetes and CLI. Additionally, we recently discovered that serum circulating FAS (cFAS) is elevated in the serum of patients with advanced diabetes and CLI. Furthermore, cept1 knockout in the endothelium leads to significantly reduced atheroprogression and normalization of serum lipid profiles. Innovation: The main objective of this proposal is to determine whether de novo lipogenesis and Fenofibrate can affect peripheral atheroprogression in the setting of diabetes. This line of investigation will be highly innovative since it will address key knowledge gaps in the mechanisms that contribute to peripheral atheroprogression in diabetes, and may help tailor therapy for surgical patients afflicted by this condition. Specific Aims: We hypothesize that CEPT1 and cFAS are key players in EC lipid metabolism and have important roles in peripheral arterial atheroprogression in the setting of diabetes and CLI. Using a complement of biochemical techniques and already generated mouse lines, we will test this hypothesis in two aims: Aim 1 will determine whether CEPT1 and cFAS can affect peripheral arterial atheroprogression in the setting of diabetes, and Aim 2 will determine whether Fenofibrate affects endothelial de novo lipogenesis and peripheral atheroprogression.

项目摘要 背景和意义：外周动脉疾病（PAD）影响美国1200万人（1/27 个人）。糖尿病患者发生终末期手术的可能性是其他患者的近10倍。 严重肢体缺血（CLI）和下肢大截肢等并发症。这导致 糖尿病手术患者的健康、心理和经济负担。因此有 更好地了解这种慢性疾病的过程，以开发更有效的治疗方法， 改善这些患者的健康状况。 非诺贝特，一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，可降低血清 甘油三酸酯是迄今为止唯一一种显示可降低外周截肢率的药物， 糖尿病然而，尚不清楚非诺贝特如何赋予这种益处，因此它很少用于治疗糖尿病。 有截肢风险的糖尿病和CLI手术患者的临床管理。 从头脂肪生成是一个多步骤的脂质合成途径，已知有助于发病机制 糖尿病在非血管器官组织中的作用，并受脂肪酸合成酶（FAS）和 胆碱/乙醇胺磷酸转移酶-1（CEPT 1）。这些酶之间的相互作用可以导致激活 PPARα介导的信号传导。目前尚不清楚非诺贝特是否会影响新生脂肪生成、内皮细胞生成和血管生成。 细胞（EC）脂质代谢和糖尿病背景下外周动脉粥样硬化进展。 初步数据：我们观察到非诺贝特确实可以影响周围肢体灌注， 改变了新生脂肪生成我们还观察到CEPT 1和FAS都在外周血中丰富， 糖尿病和CLI患者的动脉内膜。另外，我们最近发现， FAS（cFAS）在晚期糖尿病和CLI患者的血清中升高。此外，cept 1敲除 在内皮细胞中的作用导致动脉粥样硬化进展的显著减少和血脂谱的正常化。 创新：本提案的主要目的是确定新生脂肪生成和非诺贝特是否 可以影响糖尿病患者外周动脉粥样硬化的进展。这条调查线将是高度 创新性，因为它将解决有助于周边国家发展的机制中的关键知识差距。 这可能有助于为患有这种疾病的手术患者提供定制治疗。 具体目的：我们假设CEPT 1和cFAS是EC脂质代谢的关键参与者， 在糖尿病和CLI背景下外周动脉粥样硬化进展中的重要作用。使用complement 利用生物化学技术和已经产生的小鼠品系，我们将在两个目标中检验这一假设： 将确定CEPT 1和cFAS是否可以影响外周动脉粥样硬化进展， Aim 2将确定非诺贝特是否影响内皮细胞新生脂肪生成和外周 动脉粥样硬化进展