Cellular and Molecular Mechanisms of Acute Lung Injury in Sickle Cell Disease

描述（由申请人提供）： 埃默里血红蛋白病卓越研究中心（CEHR）致力于通过开发针对镰状细胞病（SCD）急性胸部综合征（ACS）主要死因的新型治疗方法和生物标志物来改善镰状细胞病（SCD）患者的健康，通过发现关键分子和细胞机制以及影响ACS的人类多样性遗传标记，并建立我们社区的转化研究能力，生物医学研究的意识和职业管道。我们的首要科学假设是血红素，组织损伤和溶血的产物，通过与Toll样受体4（TLR4）的相互作用诱导ACS。Emory CEHR汇集了一个由遗传学家，血液学医生和科学家以及肺生物学家组成的多学科团队，以严格测试这一假设，并在三个相互关联的特定目标中探索其治疗潜力：[1]定义细胞和分子机制，以及血红素诱导的内皮功能障碍和肺损伤的抑制剂。[2]确定TLR4在SCD小鼠ACS发展中的作用，并为新疗法提供临床前数据。[3]确定与ACS发病率和严重程度相关的遗传多态性。转化研究技能发展核心旨在培养临床研究方面的医学博士和博士科学家，并为他们提供指导性的研究经验，使他们成为独立的研究人员。MD学者的培训将强调I期临床试验设计，执行和分析，学者将参与研究项目中出现的候选药物的I期试验设计。博士学者，追求临床研究和基因组学的培训，也将被定位为参与CEHR的研究。镰状细胞夏季研究培训计划为高中生链接与职业发展的少数民族学生在莫尔豪斯医学院的强大计划。总之，Emory CEHR的拟议项目将严格测试肺损伤的新机制，确定干扰它的候选药物，并在科学和人力资源方面为开发预防或治疗镰状细胞病ACS的全新治疗方法奠定坚实的基础。(End摘要）

DESCRIPTION (provided by applicant): The Emory Center of Excellence in Hemoglobinopathy Research (CEHR) aspires to improve the health of individuals with sickle cell disease (SCD) by developing novel therapeutics and biomarkers for the major cause of death in SCD acute chest syndrome (ACS), through the discovery of critical molecular and cellular mechanisms, and genetic markers of human diversity that influence ACS, and to build capacity in our community in translational research, awareness and career pipelines in biomedical research. Our overarching scientific hypothesis is that heme, a product of tissue damage and hemolysis induces ACS via interaction with toll-like receptor 4 (TLR4). The Emory CEHR assembles a multi-disciplinary team of geneticists, hematology physicians and scientists, and lung biologists to rigorously test this hypothesis and explore its therapeutic potential in three inter-related Specific Aims: [1] Define cellular and molecular mechanisms, and inhibitors of heme-induced endothelial dysfunction and lung injury. [2] Determine the role of TLR4 in the development of ACS in SCD mice and generate pre-clinical data for novel therapeutics. [3] Identify genetic polymorphisms associated with the incidence and severity of ACS. A Translational Research Skills Development Core aims to train an MD and a PhD scientist in clinical research and provide mentored research experience for them to become independent investigators. Training for the MD scholar will emphasize phase I clinical trial design, execution and analysis, and the scholar will participate in the design of a Phase I trial of candidate drug(s) emerging from the research project. The PhD scholar, pursuing training in clinical research and genomics, will also be positioned to participate in the research studies of the CEHR. The Sickle Cell Summer Research Training Program for high school students links with a robust program of career development for minority students at Morehouse School of Medicine. In summary, the proposed project of the Emory CEHR will rigorously test a novel mechanism of lung injury, identify candidate drugs that interfere with it, and lay a solid foundation - in both scientific and human resources - for the development of an entirely new therapeutic approach to preventing or treating ACS in sickle cell disease. (End of Abstract)