Thrombotic complication of uremia: role of prothrombotic uremic solutes

尿毒症的血栓并发症：促血栓尿毒症溶质的作用

• 批准号: 9244842
• 负责人: Vipul C Chitalia
• 金额: $ 43.5万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-16 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244842
• 关键词: Abate; Acetates; Alteplase; Angioplasty; Animal Disease Models; Animal Model; Animals; Antiplatelet Drugs; Area; Arteries; Aryl Hydrocarbon Receptor; Asses; Balloon Angioplasty; Beds; Binding; Binding Proteins; Biological Markers; Biology; Biometry; Blood Platelets; Blood Vessels; Cardiovascular Manifestation; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Research; Coagulation Process; Complication; Data; Development; Dialysis procedure; Elements; Endothelial Cells; Environment; Epidemiologist; Event; Exhibits; Fibrinolytic Agents; Framingham Heart Study; Genetic Transcription; Glomerular Filtration Rate; Health system; Heat Shock 70kD Protein Binding Protein; High Prevalence; Human; Indican; Injury; Intervention; Knock-out; LacZ Genes; Life; Logistic Regressions; Mediator of activation protein; Modeling; Molecular; Mus; Muscle Cells; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nature; Nephritis; Nephrotoxic; Nuclear Translocation; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Population; Procedures; Property; Public Health; Receiver Operating Characteristics; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regression Analysis; Regulation; Reporting; Research; Research Personnel; Risk; Risk Factors; Risk Marker; Role; Sampling; Scientist; Sensitivity and Specificity; Serum; Signal Pathway; Signal Transduction; Therapeutic; Thromboplastin; Thrombosis; Thrombus; Time; Toxin; Transgenic Animals; Tryptophan; Ubiquitination; Uremia; Vascular Smooth Muscle; Venous; Work; Xenobiotics; base; cohort; experience; ferric chloride; high risk; improved; in vivo; indoxyl; interdisciplinary approach; nephrotoxicity; new therapeutic target; non-compliance; novel; novel marker; post intervention; potential biomarker; predictive marker; public health relevance; randomized trial; receptor binding; solute; stent thrombosis; therapeutic target; thrombolysis; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Of several cardiovascular manifestations in chronic kidney disease (CKD), thrombosis represents a potentially life threatening complication. CKD environment (uremia) is a profoundly thrombogenic. For example, next to medication noncompliance, CKD is both the second highest risk factor (increasing the risk for stent thrombosis by 6-10 folds) and an independent risk factor, which strongly suggests the presence of CKD-specific mediators. Despite its magnitude (more than 20 million people, 10% of US population with CKD) and adverse repercussions on the national public health system, mediators of uremic thrombosis have remained elusive, hampering the progress in the fields of predictive biomarkers. Furthermore, anti-thrombotic therapeutics in CKD also poses challenges. Antiplatelet and antithrombotic agents exhibit suboptimal efficacy in CKD patients, underscoring a need for a CKD-specific therapeutic target. Therefore, thrombosis in CKD is an area of high unmet clinical need both from pathogenic and therapeutic perspectives. CKD is characterized by retention of several solutes/metabolites called `uremic solutes/toxins'. Highly protein-bound nature of some of them precludes their effective clearance with dialysis. Thus, perturbing their intracellular signaling represents the most practical approach to abate the induced thrombogenicity. We were the first to identify the prothrombotic property of indolic solutes such as indoxyl sulfate (IS), which induce tissue factor (TF, a potent procoagulant) to enhance thrombosis. Our very recent work uncovered Aryl Hydrocarbon Receptor (AHR) as a key mediator of this regulation and supported IS-AHR-TF, a CKD- specific thrombosis axis. A novel panel of AHR blockers (AHRBs) showed anti-thrombotic activities. The present proposal examines this uremic thrombosis axis mechanistically and translationally leveraging animal models and samples from a large cohort of human patients. Aim 1 performs a mechanistic deconvolution of TF regulation by AHR, Aim 2 examines the in vivo relevance of AHR-TF-thrombosis in animal models of CKD, and Aim 3 correlates the serum IS, IA levels, AHR and TF activities with post-angioplasty thrombosis in Thrombosis in Myocardial Infarction-II (TIMI)-II cohort. This will be first study to analyze the uremic metabolites and validate IS-AHR-TF-thrombosis axis in a large US cohort. The present study will also support IS as a potential biomarker and AHR as a therapeutic target for uremic thrombosis. This interdisciplinary application will be facilitated by expertise of Drs. Vipul Chitalia, PI; a nephrologist and a junio physician-scientist focused on thrombosis in CKD patients), Katya Ravid, in platelet and vascular biology (co-investigator), David Sherr (co-investigator), in AHR biology, and Janice Weinberg, expert in Biostatistics and analysis of clinical studies; and consultants - David Salant, an experienced investigator in CKD animal models, Elazer Edelman, an experienced investigator in stent thrombosis and Naomi Hamburg, a clinical epidemiologist and cardiologist experienced in various translational cardiovascular studies such as Framingham Heart Study.

 描述（由应用提供）：在慢性肾脏疾病（CKD）中的几种心血管表现中，血栓形成代表了潜在的威胁生命的并发症。 CKD环境（尿emia）是一种深刻的血栓形成。例如，除了药物不合规之后，CKD既是第二高风险因素（增加支架血栓形成的风险增加了6-10倍），也是独立的危险因素，这强烈表明存在CKD特异性介体的存在。尽管它的幅度（超过2000万人，美国人口中有10％的CKD）和对国家公共卫生系统的不利影响，但尿毒症血栓形成的介体仍然难以捉摸，这阻碍了预测性生物标志物领域的进步。此外，CKD中的抗栓性疗法也带来了挑战。抗血小板和抗血栓形成剂在CKD患者中表现出次优效率，突显了对CKD特异性治疗靶标的需求。因此，CKD中的血栓形成是从致病性和治疗的角度来看，是一个高未满足临床需求的领域。 CKD的特征在于保留几种称为“尿毒症太阳能/毒素”的太阳能/代谢产物。其中一些蛋白质的高度结合性质排除了它们对透析的有效清除率。这是扰动其细胞内信号传导，代表了减轻诱导的血栓形成性的最实际方法。我们是第一个识别吲哚溶剂（例如硫酸盐）（IS）的脑栓性特性的人，该特性会诱导组织因子（TF，潜在的proco剂）增强血栓形成。我们最近的工作发现了芳基烃受体（AHR）作为该调节的关键介体，并支持CKD特异性血栓形成轴IS-AHR-TF。一个新颖的AHR阻滞剂（AHRB）的小组显示了抗脉动活动。本提案检查该尿毒症血栓形成轴机械地，并通过大量人类患者的动物模型和样本进行翻译。 AIM 1通过AHR对TF调节进行机械反卷积，AIM 2检查了CKD动物模型中AHR-TF-栓塞的体内相关性，AIM 3相关的血清IA是IA水平，AHR和TF的活性与后血管血管血栓成形术与心肌肌臂肌中血管造成的血栓形成型在心肌梗死 - Inuctruction-iii（timiiiiiii cohort）。这将是第一个研究，以分析尿毒症代谢产物并验证一个大型美国队列中的IS-AHR-TF-脑栓塞轴。本研究还将支持作为潜在的生物标志物和AHR作为尿毒症血栓形成的治疗靶标。该跨学科申请将由DRS的专业知识编写。 Vipul Chitalia，pi; Katya Ravid，血小板和血管生物学（共同评估者），David Sherr（共同评估者），AHR生物学和Janice Weinberg，在生物统计学和临床​​研究分析领域的专家；和顾问 - 大卫·萨兰特（David Salant）， CKD动物模型的经验丰富的研究者Elazer Edelman是一名经验丰富的支架血栓形成研究员，而Naomi Hamburg是一位临床流行病学家和心脏病专家Naomi Hamburg，在各种翻译的心血管研究中经历了经验丰富，例如Framingham Heart研究。