Kruppel-like factor 11 (KLF11) and atherosclerosis

项目摘要/摘要 包括儿童和成人在内的2900多万美国人患有糖尿病，而且其流行率仍然很高 在美国呈上升趋势。心血管疾病是老年人死亡的主要原因。 糖尿病患者，几乎占死亡人数的三分之二。特别是，糖尿病会加剧糖尿病的发展。 动脉粥样硬化是心脏病发作、中风和外周血管疾病的常见原因。因此， 将心血管疾病的风险降至最低是糖尿病患者管理中的一个重要临床目标。到目前为止，没有 特定的糖尿病药物或药物组合被认为优于负担得起心血管疾病 福利。越来越多的研究，包括我们的研究，发现了KLF11是 调节胰腺β细胞中的葡萄糖信号和肝脂代谢。KLF11基因多态性 与人类的T2D有关。事实上，KLF11基因突变导致了MODY7，一种早发性T2D。然而， KLF11在糖尿病相关心血管并发症中的作用和详细机制仍然存在 很大程度上没有开发。我们的初步工作确定KLF11是一种内皮细胞中的抗炎因子 (EC)在这里，我们提出了KLF11是一个葡萄糖反应基因，具有强大的抗氧化剂和 血管内皮细胞体外抗炎作用和体内KLF11缺乏加重糖尿病动脉粥样硬化。 因此，我们假设KLF11通过抑制内皮细胞来保护血管免受动脉粥样硬化的影响。 通过TXNIP的氧化应激，通过系统地实施KLF11的得失来解决 糖尿病和正常血糖条件下的体外和体内功能策略。首先，我们将定义 KLF11在体外培养内皮细胞氧化应激中的作用及分子机制(目标1)。接下来，利用我们独特的 EC特异性KLF11转基因和基因敲除小鼠模型，可用于并专门为本研究生成， 我们将确定KLF11在饮食诱导的动脉粥样硬化发展中的作用(目标2)。基于 初步结果和整个领域，我们期待KLF11在糖尿病相关疾病中发挥保护作用 动脉粥样硬化主要通过调节氧化还原基因，特别是下调硫氧还蛋白的相互作用来实现 蛋白质(TXNIP)在促动脉粥样硬化刺激下的作用。这项研究将提供更大的机械洞察力 进入内皮细胞中的整体KLF11生物学，并与产生的新资源一起，将有助于 未来设计治疗糖尿病和相关心血管疾病的新药。

PROJECT SUMMARY/ABSTRACT More than 29 million Americans, including children and adults, are living with diabetes and its prevalence is still on the rise in the United States. Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients, accounting for almost 2 out of 3 deaths. In particular, diabetes aggravates the development of atherosclerosis, which is the usual cause of heart attack, stroke, and peripheral vascular diseases. Thus, minimization of the risk of CVD is a critical clinical goal in the management of diabetic patients. To date, no particular diabetes medication or combination of medications is considered superior to afford cardiovascular benefits. An increasing body of studies, including ours, uncovered evidence that KLF11 is a key factor in regulating glucose signaling in pancreatic β-cells and hepatic lipid metabolism. KLF11 gene polymorphisms are associated with human T2D. Indeed, KLF11 gene mutation causes MODY7, an early-onset T2D. However, the functions and detailed mechanisms of KLF11 in diabetes-associated cardiovascular complications remain largely unexploited. Our preliminary work identifies KLF11 as an anti-inflammatory factor in endothelial cells (EC) and here we present evidences that KLF11 is a glucose responsive gene, displays potent antioxidant and anti-inflammatory effects in EC in vitro and KLF11 deficiency aggravates diabetic atherosclerosis in vivo. Hence, we hypothesize that KLF11 protects the vasculature from atherogenesis by inhibiting endothelial cell oxidative stress through TXNIP, to be addressed by systematically implementing gain- and loss-of-KLF11 function strategies both in vitro and in vivo under diabetic and euglycemic conditions. First, we will define the role and molecular mechanisms of KLF11 in ECs oxidative stress in vitro (Aim 1). Next, leveraging our unique EC-specific KLF11 transgenic and knockout mouse models, available and specifically generated for this study, we will determine the role of KLF11 in the development of diet-induced atherosclerosis (Aim 2). Based on preliminary results and the field at large, we expect that KLF11 exerts protective effects in diabetes-associated atherosclerosis mainly through modulating redox genes, especially down-regulating thioredoxin interacting protein (TXNIP) in the presence of proatherogenic stimuli. This study will provide greater mechanistic insight into the overall KLF11 biology in the endothelium and, together with the new resources generated, will aid in future design of novel drugs to treat diabetes and associated CVD.