Asthma, Basophils, and Leukocyte-lg-Like Receptors

哮喘、嗜碱性粒细胞和白细胞 lg 样受体

• 批准号: 7173852
• 负责人: DAVID E. SLOANE
• 金额: $ 12.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173852
• 关键词: Affinity; Allergic; Allergy and Immunology; Anabolism; Asthma; Attenuated; Basic Science; Basophils; Binding; Biochemical; Biological; Case-Control Studies; Cell Surface Receptors; Cell surface; Cells; Cytokine Gene; Data; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Enzyme Immunoassay; Family; Fc Receptor; Fellowship; Flow Cytometry; Gene Expression; Gene Expression Regulation; Glycoproteins; Histamine; Histamine Release; Hospitals; Human; IL8 gene; IgE Receptors; Immune system; Immunoglobulins; Individual; Inflammation; Inflammatory; Interleukin-13; Interleukin-3; Interleukin-4; Internal Medicine; Kinetics; Laboratories; Leukocytes; Leukotriene C4; Ligands; Ligation; Mediating; Mediator of activation protein; Molecular; Monoclonal Antibodies; Numbers; Pathogenesis; Patients; Pattern; Physicians; Polymerase Chain Reaction; Program Development; Research; Research Design; Research Methodology; Research Personnel; Residencies; Role; Scientist; Signal Transduction; Source; Surface; Techniques; Time; Training Programs; Translational Research; Universities; Upper arm; Woman; atopy; base; career; crosslink; cytokine; immunoglobulin receptor; insight; interest; novel; novel therapeutics; outcome forecast; peripheral blood; receptor; skills; therapeutic target

DESCRIPTION (provided by applicant): This proposal details a 5 year training program for the development of an academic career in Allergy and Immunology. The principle investigator completed a residency in Internal Medicine and a fellowship in Allergy and Immunology at Harvard University and now plans to augment his skills in basic science and translational research on asthma. Allergic inflammation underlies asthma, and basophils are implicated in its pathogenesis. The Leukocyte Immunoglobulin-like Receptors (LIRs) are a family of immunoregulatory cell surface receptors. Recent research in Dr. Jonathan Arm's laboratory has demonstrated that human peripheral blood basophils express LIR3 (inhibitory) and LIR7 (activating). Stimulation of basophils through LIR7 induces the release of histamine, LTC4, and IL-4. Co-ligation of LIR3 to an activating receptor such as LIR7 or the high affinity IgE receptor (Fc-epsilonRI) attenuates release of these mediators. The applicant's long term objective is to understand the roles of the LIRs in the pathogenesis of asthma in an attempt to identify novel therapeutic targets. The specific aims of the proposed research are: 1) Establishing the expression and function of LIR7 on peripheral blood basophils from normal human donors, 2) Establishing the expression and function of inhibitory LIRs on peripheral blood basophils from normal human donors, and 3) Determining the expression and function of activating and inhibitory LIRs on peripheral blood basophils from individuals with asthma, atopy, and both asthma and atopy, as compared with normal individuals. The proposed research methods are: In Aims 1 and 2, basophils from normal individuals will be analyzed for surface expression of LIRs by flow cytometry. The time- and concentration-dependent release of mediators will be assessed by enzyme immunoassay after LIR-based stimulation and inhibition. LIR-mediated signal transduction and cytokine gene regulation in basophils will be investigated employing a variety of cellular, molecular, and biochemical approaches with the expert assistance of Howard R. Katz, Ph.D., Donald W. MacGlashan, Jr., M.D., Ph.D. and James W. Homer. The proposed research design for Specific Aim 3 is a case control study comparing the results of basophil activation and inhibition (as in Aims 1 and 2) among the four groups of subjects. The Brigham and Women's Hospital Division of Allergy and Immunology is an ideal setting from which the principle investigator may launch his career as a physician scientist.

描述（由申请人提供）：该提案详细介绍了为期5年的培训计划，以开发过敏和免疫学领域的学术生涯。这位主要研究人员完成了哈佛大学的内科居住和过敏和免疫学研究金，现在计划增强他在哮喘上的基础科学和转化研究方面的技能。过敏性炎症是哮喘和嗜碱性粒细胞的基础，与其发病机理有关。白细胞免疫球蛋白样受体（LIR）是免疫调节细胞表面受体的家族。乔纳森ARM博士的实验室的最新研究表明，人类外周血嗜碱性粒细胞表达LIR3（抑制性）和LIR7（激活）。通过LIR7刺激嗜碱性粒细胞诱导组胺，LTC4和IL-4的释放。 LIR3与激活受体的共同结合，例如LIR7或高亲和力IgE受体（FC-EPSILONRI），可减弱这些介体的释放。申请人的长期目标是了解LIR在哮喘发病机理中的作用，以鉴定新的治疗靶标。拟议的研究的具体目的是：1）确定正常供体的LIR7对周围血液嗜血粒子的表达和功能，2）建立抑制性LIR对正常人类供体的外周血嗜血粒子的表达和功能，以及3）确定在激活和抑制性层次上的表达和抑制作用的表达和功能。与正常人相比。提出的研究方法是：在目标1和2中，将通过流式细胞仪分析来自正常个体的嗜碱性粒细胞以表达LIR的表面表达。介体的时间和浓度依赖性释放将在基于LIR的刺激和抑制后通过酶免疫测定评估。 LIR介导的信号转导和嗜碱性粒细胞的细胞因子基因调节将在霍华德·R·卡兹（Howard R.和詹姆斯·W·荷马。针对特定目标3的拟议研究设计是一项案例控制研究，比较了四组受试者中嗜碱性粒细胞激活和抑制作用（如目标1和2中）的结果。 Brigham和妇女医院过敏和免疫学是一个理想的环境，主要调查员可以从中启动他作为医师科学家的职业。