CC Chemokine-Mediated Differential Immunoregulation by Human Eosinophils

CC 趋化因子介导的人嗜酸性粒细胞的差异免疫调节

• 批准号: 9133088
• 负责人: Praveen Akuthota
• 金额: $ 12.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133088
• 关键词: CC; Chemokine; Mediated; Differential; Immunoregulation

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.

描述（由申请人提供）：候选人（Praveen Akuthota博士）是肺部，重症监护和睡眠医学部的成员，以及贝丝以色列女执事医疗中心的过敏和炎症部门，是医学的教练在哈佛医学院。这个K08职业发展奖将促进他的职业目标，成为嗜酸性粒细胞免疫生物学的独立研究者。在奖励期间，职业发展计划将通过在彼得·韦勒（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本研究人员的技能。贝丝以色列执事医学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组成部分的成功。该研究计划着重于人类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中的终极效应细胞，可通过释放细胞毒性物质作用。但是，越来越多的证据表明，嗜酸性粒细胞具有重要的多能免疫调节作用。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。该滞后可能部分导致对包括哮喘在内的病理生物学嗜酸性肺部疾病的病理生物学不完全理解。候选人以前的工作已经确定了CCR7（CCL19和CCL21）的配体是趋化因子，其对嗜酸性粒细胞的影响及其影响局部免疫环境的能力。拟议的研究将解决以下总体假设：嗜酸性粒细胞上的CCR7受体 - 配体相互作用在过敏气道疾病中具有不可或缺的作用，从而促进了Th2炎症和组织嗜酸性粒细胞增多的分辨率。为了解决这一总体假设，具体目的将研究以下机制：1）人类嗜酸性粒细胞表达具有CCL19和CCL21刺激的促分辨率表型； 2）暴露于CCR7配体的人嗜酸性粒细胞可预防淋巴细胞的Th2极化； 3）CCR7缺陷型嗜酸性粒细胞小鼠的过敏性气道炎症增加。这些研究将利用从人类供体的外周血和过敏性气道炎症模型中分离出来的人类嗜酸性粒细胞。特定的实验设计包括基于多重细胞因子分泌的多重研究，嗜酸性基因表达分析，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养转移的鼠研究。拟议的研究有可能提供对特定趋化因子刺激的差异嗜酸性粒细胞反应的见解，并提高人们对嗜酸性粒细胞和肺部疾病相交的理解。