Disease-specific risk factors for thrombosis following vascular interventions

血管介入治疗后血栓形成的疾病特异性危险因素

基本信息

批准号：
10733113
负责人：
Vipul C Chitalia
金额：
$ 69.41万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733113
关键词：
Address Affect American Angioplasty Animal Model Arteries Aryl Hydrocarbon Receptor Biogenesis Biological Markers Blood Blood Vessels Cardiovascular Diseases Carotid Artery Thrombosis Cessation of life Chronic Kidney Failure Clinical Clinical Trials Complication Coronary artery Data Dialysis procedure Disease Enzymes Event Extracellular Matrix Frequencies Gene Silencing Generations Genetic Hemostatic function Human ITIM Indican Inflammation Inflammatory Intervention Investigation Knockout Mice Kynurenine Ligation Mediating Mediator Modeling Molecular Mus Operative Surgical Procedures Organ PDGFRB gene Pathology Pathway interactions Patients Persons Phosphorylation Plasminogen Activator Inhibitor 1 Platelet-Derived Growth Factor beta Receptor Procedures Production Protein-Lysine 6-Oxidase Proteins Regulation Renal function Research Risk Risk Factors Signal Transduction Thromboplastin Thrombosis Time Toxic effect Toxin Tryptophan Tryptophan 2,3 Dioxygenase Tyrosine Up-Regulation Uremia Veins Venous Thrombosis Work burden of illness cost cytokine experience high risk human model inhibitor innovation knockout gene mortality mouse model new therapeutic target novel pharmacologic post intervention solute therapeutic target thrombogenesis thrombotic trend ubiquitin-protein ligase vascular injury

项目摘要

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.

抽象的血管血栓形成和止血改变与多种器官病理有关，其中具体的中介因素仍然知之甚少。这方面与慢性肾病尤其相关慢性肾病 (CKD)，影响着 3000 万美国人。 CKD患者心血管疾病发病率高负担，使 CKD 患者需要频繁的血管介入治疗，例如血管内手术或血管手术。 CKD 环境（尿毒症）是血栓形成后的一个强大而独立的危险因素。程序。鉴于 CKD 总体呈上升趋势，且介入治疗频率较高，研究此类干预后并发症及其控制方法是值得追求的。 CKD 的特点是大量尿毒症溶质的滞留。尽管对人类和动物的研究模型表明尿毒症溶质硫酸吲哚酚和犬尿氨酸是 CKD 特异性危险因素，并且是，因此，它们被认为是心血管疾病诱人的治疗靶点，其确切机制行动仍然知之甚少。当前提案将解决这一基础问题。我们的工作在近年来阐明了吲哚尿毒症毒素的促血栓形成倾向，部分介导了其毒性通过上调 vSMC 中的组织因子。在这里，基于新数据，我们提出了一种综合方法研究新发现的会增加 CKD 血栓形成的汇聚途径，其中包括吲哚胺 2,3- 双加氧酶-1 (IDO1)（犬尿氨酸生成中的关键酶）和赖氨酰氧化酶 (LOX)（关键酶调节剂）细胞外基质重塑和血栓形成。目标 1 检查 IDO1 水平和活性的新调节硫酸吲哚酚和/或犬尿氨酸及其对尿毒症血栓形成的贡献，利用遗传和 CKD 小鼠模型中 IDO1 的药理学操作。目标 2 建立在我们的新发现之上，表明 LOX 表达作为硫酸吲哚酚和犬尿氨酸的靶标，从而有助于尿毒症诱导的血管血栓形成。该目标采用分子和基因敲除方法来了解 LOX 的控制尿毒症环境中 VSMC 的生物发生及其对 CKD 背景下血栓形成的贡献。两个目标研究将利用 CKD 小鼠的动脉和静脉血栓形成模型。顺利完成本提案将定义 CKD 相关的常见血栓形成介质。随着机械的进步，我们提出的研究可能为重新利用先进的临床化合物来治疗血管疾病铺平道路 CKD 患者的闭塞。