Targeted Anticoagulant Therapy for Sickle Cell Disease

描述（由申请人提供）： 本申请由北卡罗来纳州（北卡罗来纳州）查佩尔山大学提交，以响应RFAHL- 13-005，题为“卓越血红蛋白病研究奖（EHRA）"。我们已经组建了一支由基础和临床科学家组成的杰出的多学科团队，他们将专注于基础机制研究，这些研究可能会导致开发治疗镰状细胞病（SCD）的新疗法。尽管SCD是一种血红蛋白疾病，但许多研究小组现已证明其与导致多灶性血管闭塞和终末器官功能障碍的复杂血管病理生理学相关。我们的研究小组已经取得了令人兴奋的新发现，在两种SCD小鼠模型中，抑制组织因子（凝血级联反应的主要细胞引发剂）不仅可以减少凝血，还可以减少炎症和内皮激活。我们的研究结果进一步表明，“串扰”之间的凝血和这些系统是介导的蛋白酶激活受体-1（PAR-1）和PAR-2。我们提出了一个新的概念，靶向抑制凝血蛋白酶和/或PAR-2代表了一个潜在的可行的和有效的策略来治疗SCD患者，目前有很少的治疗选择。在临床前研究中，我们将评价特异性靶向外源性、内源性或最终共同凝血途径的药物对凝血和炎症以及内皮活化的影响。在一项补充的概念验证临床试验中，使用新的Xa因子（FXa）抑制剂利伐沙班，我们将确定FXa抑制的效果是否超出SCD患者的简单抗凝治疗。杰出的学术环境，将利用发展培训研究核心，将监督年轻的医学博士和博士研究人员的招聘和职业发展，追求血红蛋白病的研究生涯（摘要结束）

DESCRIPTION (provided by applicant): This application from the University of North Carolina (UNC) at Chapel Hill is submitted in response to RFAHL- 13-005, entitled "Excellence in Hemoglobinopathies Research Award (EHRA)". We have assembled an outstanding multi-disciplinary team of basic and clinical scientists, who will focus on basic mechanistic studies that may lead to the development of new therapies for the treatment of sickle cell disease (SCD). Although SCD is a hemoglobin disorder, many groups have now demonstrated that it is associated with a complex vascular pathophysiology that results in multifocal vascular occlusion and end organ dysfunction. Our group has made the exciting, new discovery that inhibition of tissue factor, which is the primary cellular initiator of the coagulation cascade, not only reduces coagulation but also inflammation and endothelial activation in two mouse model of SCD. Our results further indicate that 'cross-talk' between coagulation and these systems is mediated by protease activated receptor-1 (PAR-1) and PAR-2. We propose the novel concept that targeted inhibition of coagulation proteases and/or PAR-2 represents a potentially viable and efficacious strategy to treat patients with SCD, for whom there are currently very few therapeutic options. In pre-clinical studies, we will evaluate the effects of agents that specifically target the extrinsic, intrinsic or final commn coagulation pathways on coagulation and inflammation, as well as endothelial activation. In a complementary proof-of-concept clinical trial with the newly available factor Xa (FXa) inhibitor rivaroxaban, we will determine whether the effect of FXa inhibition extends beyond simple anticoagulation in patients with SCD. The outstanding academic environment at UNC will be leveraged to develop a Training Research Core that will supervise the recruitment and career development of young MD and PhD investigators pursuing a research career in hemoglobinopathies (End of Abstract)