Disease-specific risk factors for thrombosis following vascular interventions

摘要 血管血栓形成和止血改变与几种器官病理有关，这种疾病- 具体的调解人仍然知之甚少。这一方面在慢性肾脏中尤其相关。 疾病(CKD)，影响着3000万美国人。慢性肾脏病患者患有高度心血管疾病 负担，使CKD患者需要频繁的血管干预，如血管内手术或 血管手术。CKD环境(尿毒症)是血栓形成的一个强烈和独立的危险因素。 程序。鉴于慢性肾脏病总体上呈上升趋势，而且介入手术的频率很高， 研究此类介入术后并发症及其控制方法是一项值得追求的工作。 CKD的特点是大量尿毒症溶质滞留。虽然对人类和动物的研究 模型暗示尿毒症溶质吲哚硫酸盐和犬尿氨酸是CKD特有的风险因素， 因此，作为心血管疾病诱人的治疗靶点，它们的确切机制 人们对这些行动仍知之甚少。这一基础将在目前的提案中得到解决。我们在中国的工作 近年来阐明了吲哚尿毒症毒素的血栓前倾向，部分介导了其毒性。 通过上调vSMC中的组织因子。在这里，我们在新数据的基础上提出了一种综合方法 研究新发现的在慢性肾脏病中增加血栓形成的汇聚途径，包括吲哚胺2，3- 生产犬尿氨酸的关键酶--双加氧酶-1(IDO1)和关键的酶调节因子赖氨酸氧化酶(LOX) 细胞外基质重塑和血栓形成。目标1研究了一种新的IDO1水平和活性调节 由吲哚基硫酸酯和/或犬尿氨酸，及其对尿毒症血栓形成的贡献，使用遗传和 IDO1在慢性肾脏病小鼠模型中的药理作用。Aim 2以我们的新发现为基础，提出 LOX表达作为吲哚硫酸盐和犬尿氨酸的靶标，从而促进尿毒症诱导的血管生成。 血栓形成。这一目的是利用分子和基因敲除方法来了解LOX的控制 尿毒症环境中VSMCs的生物发生及其对CKD背景下血栓形成的贡献。两个目标都是 研究将利用CKD小鼠的动脉和静脉血栓模型。成功完成本建议书 将定义CKD相关的血栓形成的常见介质。随着机械性的进步，我们提出的 研究可能为将先进的临床化合物用于血管管理铺平道路。 慢性肾脏病患者的闭塞。

Abstract Vasculo-thrombosis and altered hemostasis are associated with several organ pathologies, the disease- specific mediators of which remain poorly understood. This aspect is particularly relevant in chronic kidney disease (CKD), which affects 30 million Americans. Patients with CKD suffer from high cardiovascular disease burden, making CKD patients in need of frequent vascular interventions, such as endovascular procedures or vascular surgery. A CKD milieu (uremia) is a strong and independent risk factor for thrombosis after such procedures. Given the upward trend of CKD in general, and high frequency of interventional procedures in them, investigating such post-interventional complications and means to control them is a worthy pursuit. CKD is characterized by retention of a host of uremic solutes. Although studies in humans and animal models implicate the uremic solutes indoxyl sulfate and kynurenine as CKD-specific risk factors and are, therefore, perceived as tantalizing therapeutic targets for cardiovascular disease, their exact mechanism of actions remains poorly understood. This underpinning will be addressed in the current proposal. Our work in recent years elucidated prothrombotic propensities of indolic uremic toxins, partially mediating their toxicity through upregulation of tissue factor in vSMCs. Here, building on new data, we propose an integrative approach to study newly identified converging pathways that augment thrombosis in CKD, consisting of Indoleamine 2,3- dioxygenase-1 (IDO1), a key enzyme in kynurenine production, and lysyl oxidase (LOX), a key enzyme regulator of extracellular matrix remodeling and thrombosis. Aim 1 examines a novel regulation of IDO1 level and activity by indoxyl sulfate and/or kynurenine, and its contribution to uremic thrombosis, using genetic and pharmacological manipulation of IDO1 in a CKD mouse model. Aim 2 builds on our new findings suggesting LOX expression as a target of indoxyl sulfate and kynurenine, thereby contributing to uremia-induced vasculo- thrombosis. This aim employs molecular and gene knockout approaches to understand the control of LOX biogenesis in VSMCs in a uremic milieu, and its contribution to thrombosis in context of CKD. Both aims of research will utilize arterial and venous thrombosis models in CKD mice. Successful completion of this proposal will define CKD-associated common mediators of thrombosis. Along with mechanistic advances, our proposed investigations might pave ways to repurposing advanced clinical compounds for the management of vascular occlusion in CKD patients.