Targeted Anticoagulant Therapy for Sickle Cell Disease

描述(由申请人提供)： 北卡罗来纳大学(UNC)教堂山分校提交的这份申请是对RFAHL-13-005号文件的响应，该文件题为“卓越的血红蛋白病症研究奖(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。虽然SCD是一种血红蛋白疾病，但许多研究小组现已证明，它与复杂的血管病理生理有关，导致多灶性血管闭塞和终末器官功能障碍。我们的团队取得了令人兴奋的新发现，抑制凝血级联反应的主要细胞启动者组织因子，不仅可以减少凝血，还可以减少炎症和内皮细胞的激活。我们的结果进一步表明，凝血和这些系统之间的“串扰”是由蛋白酶激活的受体-1(PAR-1)和PAR-2介导的。我们提出了靶向抑制凝血酶和/或PAR-2的新概念，这是治疗SCD患者的一种潜在可行和有效的策略，目前对SCD患者的治疗选择很少。在临床前研究中，我们将评估针对外源性、内源性或终末凝血通路的药物对凝血和炎症以及内皮激活的影响。在一项与新近可用的因子Xa(FXA)抑制剂利伐沙班进行的补充概念验证临床试验中，我们将确定FXA抑制对SCD患者的影响是否超出了简单的抗凝。北卡罗来纳大学杰出的学术环境将被用来开发一个培训研究核心，该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，这些研究人员寻求在血红蛋白疾病方面的研究生涯(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)