Targeted Anticoagulant Therapy for Sickle Cell Disease

镰状细胞病的靶向抗凝治疗

• 批准号: 8467839
• 负责人: Kenneth I Ataga
• 金额: $ 169.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467839
• 关键词: Anticoagulant therapy; Anticoagulation; Antithrombin III; Award; Blood Vessels; Clinical; Clinical Trials; Coagulation Process; Complex; Development; Disease; Doctor of Philosophy; Environment; Equipment; Factor Xa; Functional disorder; Hemoglobin; Hemoglobinopathies; Inflammation; Instruction; International; Lead; Location; Malawi; Mediating; North Carolina; Organ; PAR-1 Receptor; Pathway interactions; Patients; Peptide Hydrolases; Principal Investigator; Research; Research Personnel; Research Training; Resources; Scientist; Sickle Cell Anemia; Site; System; Therapeutic; Thromboplastin; Training; Universities; abstracting; career; career development; mouse model; novel; preclinical study; programs; response

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)

描述（由申请人提供）： 北卡罗来纳大学（UNC）在教堂山（UNC）的申请是为了响应RFAHL-13-005，题为“血红蛋白疗法卓越研究奖（EHRA）”。我们组建了一个由基本和临床科学家组成的杰出的多学科团队，他们将重点关注基本的机械研究，这可能导致开发用于镰状细胞疾病（SCD）的新疗法。尽管SCD是一种血红蛋白疾病，但许多组现已证明它与复杂的血管病理生理学有关，该病理生理学导致多灶性血管闭塞和最终器官功能障碍。我们的小组提出了一个令人兴奋的新发现，即抑制组织因子是凝血级联反应的主要细胞引发剂，不仅减少了凝血凝血，而且还会减少两个小鼠SCD模型中的炎症和内皮激活。我们的结果进一步表明，凝血和这些系统之间的“跨词”是由蛋白酶激活的受体1（PAR-1）和PAR-2介导的。我们提出了针对抑制凝血蛋白酶和/或PAR-2的新型概念，代表了一种潜在的可行和有效的策略来治疗SCD患者，目前几乎没有治疗选择。在临床前研究中，我们将评估特异性针对外在，内在或最终通心凝结途径对凝结和炎症以及内皮激活的药物的作用。在与新近可用的因子XA（FXA）抑制剂Rivaroxaban进行的补充概念验证临床试验中，我们将确定FXA抑制作用的作用是否超出了SCD患者的简单抗凝作用。 UNC的杰出学术环境将被利用，以开发培训研究核心，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，从事血红蛋白研究的研究生涯（摘要的结束）