Thrombotic complication of uremia: role of prothrombotic uremic solutes

 描述（由申请方提供）：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危及生命的并发症。CKD环境（尿毒症）是一种严重的血栓形成。例如，仅次于药物不依从性，CKD既是第二高风险因素（支架血栓形成风险增加6-10倍），也是一个独立的风险因素，这强烈表明存在CKD特异性介质。尽管其规模（超过2000万人，占美国CKD人口的10%）和对国家公共卫生系统的不良影响，尿毒症血栓形成的介质仍然难以捉摸，阻碍了预测生物标志物领域的进展。此外，CKD的抗血栓治疗也带来了挑战。抗血小板和抗血栓药物在CKD患者中表现出次优疗效，强调了对CKD特异性治疗靶点的需求。因此，CKD中的血栓形成是一个从致病和治疗角度都高度未满足的临床需求领域。CKD的特征是几种称为“尿毒症溶质/毒素”的溶质/代谢物的滞留。它们中的一些的高度蛋白结合性质妨碍了它们通过透析的有效清除。因此，干扰它们的细胞内信号传导代表了减轻诱导的血栓形成的最实用的方法。 我们是第一个鉴定吲哚类溶质如硫酸吲哚酚（IS）的促血栓形成特性的人，其诱导组织因子（TF，一种有效的促凝血剂）以增强血栓形成。我们最近的工作揭示了芳烃受体（AHR）作为这种调节的关键介质，并支持IS-AHR-TF（CKD特异性血栓形成轴）。一组新的AHR阻断剂（AHRB）显示出抗血栓形成活性。目前的建议审查这尿毒症血栓轴机制和预防利用动物模型和样本从一个大的人类患者队列。目的1通过AHR对TF调节进行机械去卷积，目的2检查CKD动物模型中AHR-TF-血栓形成的体内相关性，目的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。这将是第一项在美国大型队列中分析尿毒症代谢物并验证IS-AHR-TF-血栓形成轴的研究。本研究也将支持IS作为尿毒症血栓形成的潜在生物标志物和AHR作为治疗靶点。Vipul Chitalia博士（PI）、Katya Ravid（血小板和血管生物学）、大卫谢尔（AHR生物学）、Janice温伯格（生物统计学和临床研究分析专家）和顾问大卫Salant（顾问）的专业知识将促进该跨学科应用。 一位在CKD动物模型方面经验丰富的研究者，一位在支架血栓形成方面经验丰富的研究者Elazer Edelman，以及一位在各种转化心血管研究（如Fracket心脏研究）方面经验丰富的临床流行病学家和心脏病学家Naomi Hamburg。

 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.