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

镰状细胞病急性肺损伤的细胞和分子机制

• 批准号: 8722610
• 负责人: Michael R. DeBaun
• 金额: $ 172.94万
• 依托单位: EMORY UNIVERSITY
• 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/8722610
• 关键词: Acute Lung Injury; Awareness; Biological Markers; Biomedical Research; Cause of Death; Clinical Data; Clinical Research; Clinical Trials Design; Communities; Development; Doctor of Philosophy; Foundations; Genetic Markers; Genetic Polymorphism; Genomics; Health; Hematology; Heme; Hemoglobinopathies; Hemolysis; High School Student; Human; Human Resources Development; Incidence; Individual; Link; Lung; Mentors; Minority; Molecular; Morehouse School of Medicine; Mus; Phase I Clinical Trials; Physicians; Positioning Attribute; Research; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Severities; Sickle Cell; Sickle Cell Anemia; Solid; Students; Testing; Therapeutic; Tissues; Training; Training Programs; Translational Research; abstracting; acute chest syndrome; career; career development; design; drug candidate; endothelial dysfunction; experience; heme a; improved; inhibitor/antagonist; lung injury; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; programs; research study; skills; toll-like receptor 4

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)

描述（由申请人提供）： 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生物医学研究中的管道。我们的总体科学假设是，血红素是组织损伤和溶血的产物，通过与Toll样受体4（TLR4）相互作用诱导AC。 Emory Cehr组成了一个遗传学家，血液学生理学家和科学家以及肺生物学家的多学科团队，以严格检验这一假设，并在三个相关的具体目的中探索其治疗潜力：[1]定义细胞和分子机制，以及炎症诱导的无剂量受损和lung dyngundung dyngnung dung dungnung dung dyngundung dung dungnung dungnung and dung dung ingnung and dung ingnung dung dyngungundung。 [2]确定TLR4在SCD小鼠中ACS开发中的作用，并生成用于新型疗法的临床前数据。 [3]确定与ACS的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训临床研究的MD和博士学位科学家，并为他们提供指导的研究经验，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，该学者将参加研究项目中出现的候选药物I期试验的设计。该博士学位学者在临床研究和基因组学方面进行培训，还将定位参加CEHR的研究。高中生的镰状细胞夏季研究培训计划与莫尔豪斯医学院的少数族裔学生的职业发展计划联系起来。总而言之，Emory CEHR的拟议项目将严格测试一种新型的肺损伤机制，确定干扰它的候选药物，并在科学和人力资源中奠定了稳固的基础，以开发一种全新的治疗方法，以防止或治疗镰状细胞病中的ACS ACS。 （抽象的结尾）