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(申请人提供)：在慢性肾脏疾病(CKD)的几种心血管表现中，血栓形成是一种潜在的威胁生命的并发症。CKD环境(尿毒症)是一种深刻的血栓形成因素。例如，CKD是仅次于药物不依从性的第二高风险因素(使支架血栓形成的风险增加6-10倍)，也是一个独立的风险因素，这强烈表明CKD特异性介质的存在。尽管尿毒症血栓形成的规模巨大(超过2000万人，占美国CKD人口的10%)，并对国家公共卫生系统产生不利影响，但尿毒症血栓形成的介体仍然难以捉摸，阻碍了预测性生物标志物领域的进展。此外，慢性肾脏病的抗血栓治疗也带来了挑战。抗血小板和抗血栓药物在CKD患者中表现出不理想的疗效，强调了对CKD特异性治疗靶点的需求。因此，慢性肾脏病的血栓形成无论从病因学角度还是从治疗角度来看都是一个高度未得到满足的临床需求领域。CKD的特点是滞留了几种称为尿毒症溶质/毒素的溶质/代谢物。其中一些蛋白的高度结合性质阻碍了它们与透析的有效清除。因此，干扰它们的细胞内信号转导是减少诱导的血栓形成的最实用的方法。我们首次鉴定了吲哚硫酸盐(IS)等吲哚类溶质的血栓前特性，它能诱导组织因子(TF，一种有效的促凝剂)促进血栓形成。我们最近的工作发现芳香烃受体(AHR)是这一调节的关键媒介，并支持IS-AHR-TF，一种CKD特异性血栓形成轴。一组新的AHR阻滞剂(AHRB)显示出抗血栓活性。本提案利用动物模型和大量人类患者的样本，从机械和翻译的角度研究了尿毒症血栓形成轴。目的1进行AHR对Tf调节的机械性去卷积，Aim 2检测CKD动物模型中AHR-Tf-血栓形成的体内相关性，Aim 3将血清IS、IA水平、AHR和Tf活性与心肌梗死II(TIMI)-II队列中血管成形术后血栓形成相关。这将是首次对尿毒症代谢物进行分析并在美国大型队列中验证IS-AHR-TF-血栓形成轴的研究。本研究还将支持IS作为一种潜在的生物标志物，AHR作为尿毒症血栓形成的治疗靶点。这一跨学科的应用将由Vipul Chitalia，Pi博士，肾病专家和专注于CKD患者血栓形成的初级内科科学家，血小板和血管生物学的Katya Ravid(共同研究员)，AHR生物学的David Sherr(共同研究员)，以及生物统计和临床研究分析专家Janice Weinberg的专业知识促进；以及顾问David Salant， Elazer Edelman是CKD动物模型方面经验丰富的研究员，Elazer Edelman是支架血栓形成方面的经验丰富的研究员，Naomi Hamburg是在各种心血管转换研究(如Framingham心脏研究)中经验丰富的临床流行病学家和心脏病专家。