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: 10586058
• 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/10586058
• 关键词: Acceleration; 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; 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; 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; Tissues; 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; pharmacologic; prevent; psychologic; revascularization surgery; targeted treatment; translational potential; 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 背景与意义：周围动脉疾病（PAD）影响美国1200万人（27分之一 糖尿病患者发展终末期手术的可能性几乎高10倍 诸如临界肢体缺血（CLI）和主要下肢截肢之类的并发症。这导致 对糖尿病手术患者的重要健康，心理和金融烧伤。因此，是 至关重要的是更好地了解这种慢性疾病过程，以开发更有效的治疗 策略，并改善这些患者的健康状况。 Fenodribrate，一种过氧化物体增殖物激活受体α（PPARα）激动剂，可降低串行 甘油三酸酯是迄今为止显示的唯一用于降低外周截肢率的药物 糖尿病。但是，尚不清楚非诺贝特如何承认这一收益，因此很少使用 有截肢风险的糖尿病和CLI外科患者的临床管理。 从头脂肪生成是一种多步脂质合成途径，已知有助于发病机理 非血管器官组织中的糖尿病，并由脂肪酸合酶（FAS）调节 胆碱/乙醇胺磷酸转移酶-1（CEPT1）。这些酶之间的相互作用会导致激活 PPARα介导的信号传导。尚不清楚非诺贝特是否会影响从头脂肪生成，内皮 细胞（EC）脂质代谢和糖尿病环境中周围动脉雌雄同体。 初步数据：我们观察到，fenodribrate确实会影响外围肢体灌注 从头脂肪形成改变。我们还观察到Cept1和Fas在外围均丰富 糖尿病和CLI患者的动脉内膜。此外，我们最近发现血清循环 晚期糖尿病和CLI患者的血清中FAS（CFA）升高。此外，CEPT1淘汰赛 在内皮中，会导致血清脂质谱的动脉孕作和归一化。 创新：该提案的主要目的是确定从头脂肪生成和非诺佛诺 在糖尿病的情况下会影响外围动脉植物。这一调查将是高度的 创新性，因为它将解决有助于周围的机制的关键知识差距 糖尿病中的动脉灌立，可能有助于针对患有这种疾病的手术患者调整治疗。 具体目的：我们假设CEPT1和CFA是EC脂质代谢的关键参与者，并且具有 在糖尿病和CLI的环境中，在周围动脉动脉雌雄同体中的重要作用。使用完成 通过生化技术和已经生成的小鼠线，我们将以两个目的测试这一假设：目标1 将确定在 糖尿病和AIM 2将确定非诺贝特是否会影响从头脂肪生成和周围的内皮 动脉攻击。