CC Chemokine-Mediated Differential Immunoregulation by Human Eosinophils

描述（由申请人提供）：候选人（Praveen Akuthota博士）是贝斯以色列女执事医疗中心肺部、重症监护和睡眠医学部以及过敏和炎症医学部的成员，也是哈佛医学院的医学讲师。本次K08职业发展奖将培养他成为嗜酸性粒细胞免疫生物学独立研究者的职业目标。在奖励期间，职业发展计划将允许他通过在Peter Weller博士的指导下进行拟议的研究并通过一系列的教学经验来磨练他作为基础研究者的技能。贝斯以色列女执事医疗中心和哈佛医学院提供的环境非常适合该奖项的研究和职业发展部分的成功。研究计划集中于人嗜酸性粒细胞的免疫生物学。长期以来，嗜酸性粒细胞一直被认为是哮喘和其他嗜酸性肺疾病的末端执行细胞，通过释放细胞毒性物质起作用。然而，越来越多的证据表明，嗜酸性粒细胞具有重要的多能性免疫调节作用。嗜酸性粒细胞对差异免疫调节的表征落后于其他免疫细胞类型。这种滞后可能是对包括哮喘在内的嗜酸性肺疾病的病理生物学理解不完整的部分原因。候选人之前的工作已经确定了CCR7的配体（CCL19和CCL21）作为趋化因子，其对嗜酸性粒细胞的影响及其影响局部免疫环境的能力值得探索。拟议的研究将解决总体假设，即CCR7受体-配体对嗜酸性粒细胞的相互作用在过敏性气道疾病中起着不可或缺的作用，促进Th2炎症和组织嗜酸性粒细胞的消退。为了解决这一总体假设，Specific Aims将研究其机制：1)人类嗜酸性粒细胞在CCL19和CCL21刺激下表达Pro-Resolution表型；2)暴露于CCR7配体的人嗜酸性粒细胞阻止淋巴细胞Th2极化；3) ccr7缺陷小鼠过敏性气道炎症增加。这些研究将利用从人类供体外周血和过敏性气道炎症小鼠模型中分离的人类嗜酸性粒细胞。具体的实验设计包括基于多重因子的细胞因子分泌研究，嗜酸性粒细胞基因表达分析，嗜酸性粒细胞-淋巴细胞相互作用研究，以及利用嗜酸性粒细胞过继转移的小鼠研究。拟议的研究有可能提供对特定趋化因子刺激的嗜酸性粒细胞差异反应的见解，并导致对嗜酸性粒细胞和肺部疾病的交叉的更好理解。

DESCRIPTION (provided by applicant): The Candidate (Dr. Praveen Akuthota) is a member of the Division of Pulmonary, Critical Care, and Sleep Medicine and of the Division of Allergy and Inflammation at Beth Israel Deaconess Medical Center and is an Instructor in Medicine at Harvard Medical School. This K08 Career Development Award will foster his career goal to become an independent investigator in eosinophil immunobiology. During the award period, the career development plan will allow for the honing of his skills as a basic investigator through carrying out the proposed research under the mentorship of Dr. Peter Weller and through a series of didactic experiences. The environment provided by Beth Israel Deaconess Medical Center and Harvard Medical School is ideally suited for the success of both the research and career development components of the award. The research plan focuses on the immunobiology of human eosinophils. Eosinophils have long been regarded to function exclusively as end-effector cells in asthma and other eosinophilic lung disorders, acting through the release of cytotoxic substances. However, mounting evidence has demonstrated that eosinophils have important multipotent immunoregulatory roles. Characterization of differential immunoregulation by eosinophils has lagged behind that of other immune cell types. This lag may be in part responsible for an incomplete understanding of the pathobiology eosinophilic pulmonary diseases, including asthma. The Candidate's previous work has identified the ligands of CCR7 (CCL19 and CCL21) as chemokines whose impacts on eosinophils and their capacity to influence the local immune environment warrant exploration. The proposed studies will address the overall hypothesis that CCR7 receptor-ligand interactions on eosinophils have an integral role in allergic airways disease that promotes resolution of Th2 inflammation and tissue eosinophilia. To address this overall hypothesis, Specific Aims will investigate the mechanism by which: 1) Human Eosinophils Express a Pro-Resolution Phenotype with CCL19 and CCL21 Stimulation; 2) Human Eosinophils Exposed to CCR7 Ligands Prevent Th2 Polarization of Lymphocytes; 3) Allergic Airway Inflammation Is Increased in Mice with CCR7-Deficient Eosinophils. These studies will utilize human eosinophils isolated from the peripheral blood of human donors and murine models of allergic airways inflammation. Specific experimental designs include multiplex-based studies of cytokine secretion, eosinophil gene expression analysis, eosinophil-lymphocyte interaction studies, and murine studies utilizing eosinophil adoptive transfer. The proposed research has the potential to provide insights into differential eosinophil responses to specific chemokine stimuli and lead to improved understanding of the intersection of eosinophilia and pulmonary disease.