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

• 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
• 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

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 Vasculo-thrombosis和止血改变与几种器官病理有关，疾病 - 其特定的介体仍然很少理解。这方面在慢性肾脏中尤其重要 疾病（CKD），影响3000万美国人。 CKD患者患有高心血管疾病 负担，使CKD患者需要经常进行血管干预，例如血管内手术或 血管手术。 CKD环境（尿emia）是这种强大而独立的血栓形成因素 程序。鉴于CKD的上升趋势一般，其中的介入程序频率很高， 调查这种干预后的并发症和控制它们的手段是值得追求的。 CKD的特征是保留了许多尿毒症溶质。尽管人类和动物的研究 模型将尿毒症溶质的硫酸硫酸盐和kynurenine视为CKD特异性危险因素，并且是 因此，被认为是心血管疾病的诱人治疗靶标的 行动仍然很少理解。当前提案将解决这一基础。我们的工作 近年来，阐明了腺毒素毒素的促血栓性倾斜度，部分介导了其毒性 通过在VSMC中的组织因子上调。在这里，以新数据为基础，我们提出了一种综合方法 研究新鉴定的融合途径，以增加CKD中血栓形成的途径，由吲哚胺2,3-组成 二氧酶-1（IDO1），一种kynurenine生产中的关键酶和赖氨酸氧化酶（LOX），一种键调节剂 细胞外基质重塑和血栓形成。 AIM 1检查了IDO1水平和活动的新型调节 通过硫酸硫酸硫酸盐和/或kynurenine及其对尿毒症血栓形成的贡献，使用遗传和 CKD小鼠模型中IDO1的药理操作。 AIM 2建立在我们的新发现暗示的基础上 LOX表达是硫酸吲哚基和雌激素的靶标的 血栓形成。此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中的生物发生及其对CKD背景下血栓形成的贡献。两者的目标 研究将利用CKD小鼠中的动脉和静脉血栓形成模型。成功完成此建议 将定义与CKD相关的血栓形成共同介质。随着机械进步，我们提出的 调查可能铺平方法来重新利用高级临床化合物进行血管的管理 CKD患者的闭塞。