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

项目摘要 背景与意义：外周动脉疾病(PAD)影响美国1200万人(27人中有1人 个人)。糖尿病患者发展为终末期外科手术的可能性几乎高出10倍 严重肢体缺血(CLI)和大腿截肢等并发症。这导致了 糖尿病外科患者的重大健康、心理和经济负担。因此，它是 最重要的是更好地了解这种慢性病的过程，以便开发更有效的治疗方法 策略，并改善这些患者的健康。 非诺贝特，一种降低血清水平的过氧化物酶体增殖物激活受体α(PPARα)激动剂 甘油三酯是迄今为止唯一能降低慢性阻塞性肺疾病患者外周截肢率的药物。 糖尿病。然而，目前还不清楚非诺贝特是如何赋予这种益处的，因此它很少在 外科糖尿病合并CLI患者截肢风险的临床处理。 新生脂肪生成是一种多步骤的脂肪合成途径，已知在发病机制中起作用。 糖尿病在非血管器官组织中的表达，并受脂肪酸合成酶(Fas)和 胆碱/乙醇胺磷酸转移酶-1(CEPT1)。这些酶之间的相互作用可以导致激活 PPARα介导的信号转导。目前尚不清楚非诺贝特是否会影响血管内皮细胞的新生脂肪生成 糖尿病背景下细胞(EC)脂代谢和外周动脉动脉粥样硬化进展。 初步数据：我们观察到非诺贝特确实可以影响周围肢体的血流灌注。 新生脂肪生成的改变。我们还观察到CEPT1和Fas在外周血中都有丰富的表达 糖尿病合并CLI患者的动脉内膜变化。此外，我们最近发现血清循环 Fas(CFAs)在晚期糖尿病和慢性阻塞性肺病患者血清中升高。此外，Cept1基因敲除 在血管内皮细胞中，可显著减少动脉粥样硬化的进展，并使血脂谱正常化。 创新：这项提案的主要目标是确定从头开始脂肪生成和非诺贝特 会影响糖尿病患者的外周动脉粥样硬化进程。这条线的调查将高度重视 创新，因为它将解决有助于外围设备的机制中的关键知识缺口 糖尿病的动脉粥样硬化进展，可能有助于对患有这种疾病的外科患者进行量身定制的治疗。 具体目标：我们假设CEPT1和CFAs是EC脂质代谢的关键角色，并具有 外周动脉粥样硬化进展在糖尿病和CLI发病中的重要作用。使用补语 关于生化技术和已经产生的小鼠品系，我们将在两个目标上检验这一假设：目标1 将确定CEPT1和CFAs是否可以影响周围动脉的动脉粥样硬化进展 糖尿病，以及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。

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.