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) 教堂山分校的这份申请是针对 RFAHL-13-005 提交的，题为“卓越血红蛋白病研究奖 (EHRA)”。我们组建了一支由基础和临床科学家组成的优秀多学科团队，他们将专注于基础机制研究，这可能会导致镰状细胞病（SCD）治疗新疗法的开发。尽管 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学相关，导致多灶性血管闭塞和终末器官功能障碍。我们的研究小组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活化。我们的结果进一步表明凝血和这些系统之间的“串扰”是由蛋白酶激活受体 1 (PAR-1) 和 PAR-2 介导的。我们提出了一个新概念，即靶向抑制凝血蛋白酶和/或 PAR-2 代表了治疗 SCD 患者的一种潜在可行且有效的策略，而目前对该患者的治疗选择很少。在临床前研究中，我们将评估专门针对外在、内在或最终共同凝血途径的药物对凝血和炎症以及内皮激活的影响。在一项使用新推出的 Xa 因子 (FXa) 抑制剂利伐沙班的补充概念验证临床试验中，我们将确定 FXa 抑制的效果是否超出了 SCD 患者的简单抗凝治疗范围。北卡罗来纳大学出色的学术环境将被用来开发一个培训研究核心，该核心将监督从事血红蛋白病研究职业的年轻医学博士和博士研究人员的招募和职业发展（摘要结束）