Lung Endothelial Barrier Function and its Deregulation by Sickle Erythrocytes

肺内皮屏障功能及其镰状红细胞的失调

• 批准号: 7882679
• 负责人: Solomon Fiifi Ofori-Acquah
• 金额: $ 10.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-19 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882679
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Adherens Junction; Adhesions; Adhesives; Adult; Adult Respiratory Distress Syndrome; Affect; Alveolar; Alveolar wall; Anatomy; Area; Award; Back; Biology; Blood Cells; Blood Vessels; Blood capillaries; CCL2 gene; Caliber; Capillary Endothelial Cell; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell-Cell Adhesion; Cells; Chemotactic Factors; Clinical; Co-Immunoprecipitations; Cytoskeletal Proteins; Data; Endothelial Cells; Endothelium; Functional disorder; Future; Genes; Goals; Green Fluorescent Proteins; HL60; Image; Immigration; Immunoglobulins; Independent Scientist Award; Infection; Inflammation; Injury; Integrins; Intercellular Junctions; Intercept; Laboratories; Laboratory Research; Leukocytes; Life; Link; Liquid substance; Lung; Mediating; Microscopic; Molecular; Monitor; Morbidity - disease rate; Mus; Pathogenesis; Patients; Phenotype; Physiological; Play; Process; Proteins; Pulmonary Hypertension; Pulmonary vessels; Rattus; Recombinants; Recruitment Activity; Request for Proposals; Research; Role; Sickle Cell; Sickle Cell Anemia; Single Nucleotide Polymorphism; Site; Stroke; Structure; System; Testing; Thick; Tight Junctions; Time; Tissues; Transcript; United States National Institutes of Health; Variant; Wages; Work; abstracting; acute chest syndrome; body system; capillary; capillary bed; career; career development; in vivo; inhibiting antibody; interstitial; lung injury; meetings; migration; monocyte; mouse model; promoter; receptor; response; skills; vascular bed

DESCRIPTION (provided by applicant): This proposal requests salary support to protect the applicant's time to focus on the proposed studies, and associated career development in sickle cell disease (SCO) research. The applicant's long-term goal is to develop and sustain an internationally recognized research laboratory focused on unraveling adhesive mechanisms that regulate blood cell-endothelial cell interactions and endothelial dysfunction in SCO. Endothelial cells fulfill a central role in the response to inflammation by controlling the number of circulating monocytes recruited to interstitial tissue compartments. Monocyte transendothelial migration is enhanced by sickle erythrocytes, which adhere tightly to endothelial cells and up-regulate expression of multiple adhesion molecules. A single nucleotide polymorphism in the promoter of the gene for the major monocyte chemoattractant CCL2 is an independent predictor of morbidity in SCO, highlighting excessive monocyte recruitment as a contributing factor in the pathogenesis of SCO. Despite this significance, the identity of adhesion molecules and cognate mechanisms responsible for regulating transendothelial monocyte migration in the lung, and the impact sickle erythrocytes have on this process and lung endothelial barrier function, remains poorly understood and is therefore the focus of this application. Activated leukocyte cell adhesion molecule (ALCAM) is expressed by activated monocytes. The applicant's laboratory has identified ALCAM at intercellular junctions in pulmonary microvascular endothelial cells, and showed that it is required for transmigration of monocytes across cultured pulmonary microvascular endothelial cells. The proposed study will enhance the applicant's research skills in a number of areas in vascular biology including creation of chimeric mice, and allow the applicant to extend the scope of a current NIH R01 award. Equally importantly, this K02 award will allow the applicant transition back into SCO research. These career objectives will be achieved by completing three specific aims namely, 1) ALCAM is an essential component of the adherens junction in lung endothelial cells, 2) Recruitment of activated monocytes into the lung is regulated by homotypic ALCAM adhesion, and 3) Develop a live imaging system to monitor monocyte transendothelial migration, and investigate the impact of sickle erythrocytes on lung endothelial barrier functions. The protected time, enhancement of research skills and reverse transition into SCO research will equip the applicant to pursue vascular wall biology research in SCO well into the future. The results of this career award will help the applicant generate chimeric SCO mice with the type of lung injury typically found in patients with SCO. Thus, the significance of this proposal extends beyond the immediate goal of unraveling the fundamental cause of pulmonary endothelial inflammation in SCO, to developing variants of the SCO mouse model that can be used to develop rationale therapy for pulmonary complications in SCD. (End of Abstract)

描述（由申请人提供）： 该提案要求薪资支持，以保护申请人的时间专注于拟议的研究，并将镰状细胞病（SCO）研究的职业发展相关联。申请人的长期目标是开发和维持国际认可的研究实验室，该研究实验室着重于揭开SCO中血细胞内皮细胞相互作用和内皮功能障碍的粘合机制。内皮细胞通过控制募集到间质组织室的循环单核细胞的数量，在对炎症的反应中发挥了核心作用。镰状红细胞增强了单核细胞的跨内皮迁移，该细胞紧密粘附在内皮细胞上并上调多个粘附分子的表达。主要单核细胞趋化剂CCL2的基因启动子中的单个核苷酸多态性是SCO中发病率的独立预测指标，强调了过度的单核细胞募集是SCO发病机理的促成因素。尽管具有这种意义，但粘附分子和同源机制的身份负责调节肺中跨内皮单核细胞的迁移，并且镰刀红细胞对这一过程和肺部内皮屏障功能具有不佳的影响，并且仍然是不理理解的，因此仍然是该应用程序的重点。活化的白细胞细胞粘附分子（ALCAM）通过活化的单核细胞表达。申请人的实验室已经在肺微血管内皮细胞的细胞间连接处确定了ALCAM，并表明单核细胞跨培养的肺微血管内皮细胞迁移是必需的。拟议的研究将在血管生物学的许多领域提高申请人的研究技能，包括创建嵌合小鼠，并允许申请人扩大当前NIH R01奖的范围。同样重要的是，该K02奖将使申请人过渡回到SCO研究。 These career objectives will be achieved by completing three specific aims namely, 1) ALCAM is an essential component of the adherens junction in lung endothelial cells, 2) Recruitment of activated monocytes into the lung is regulated by homotypic ALCAM adhesion, and 3) Develop a live imaging system to monitor monocyte transendothelial migration, and investigate the impact of sickle erythrocytes on lung内皮屏障功能。受保护的时间，提高研究技能以及向SCO研究的过渡将使申请人能够在未来的SCO中进行血管壁生物学研究。该职业奖的结果将帮助申请人生成嵌合SCO小鼠，并以通常发现的肺部损伤类型 SCO患者。因此，该提案的重要性超出了SCO中肺内皮炎症的基本原因的直接目标，即开发SCO小鼠模型的变体，这些变体可用于开发SCD中肺部并发症的原理治疗。 （抽象的结尾）