Mechanisms of Human Basophil-Mediated Allergic Inflammation

人类嗜碱性粒细胞介导的过敏性炎症的机制

基本信息

  • 批准号:
    8631752
  • 负责人:
  • 金额:
    $ 40.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-12-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this laboratory over the past 20 years has been the elucidation of mechanisms regulating allergic inflammation and thereby identification of novel targets for treating allergic diseases. This proposal will focus on mechanisms regulating human basophil activation and effector function in allergic diseases. Basophils are the least abundant granulocytes in the circulation, and only recently has evidence demonstrated that basophils have potent effector functions that bridge innate and adaptive immunity and contribute to the pathogenesis of both allergic and autoimmune diseases. Preliminary studies demonstrate that IL-3 is a key cytokine for polarizing basophils for effector functions that include degranulation in response to FcεR1 crosslinking, regulation of cell surface molecule expression, cytokine expression, and immune modulation. Key preliminary findings include: 1) detailed analysis of IL-3 activation of human basophils that demonstrates IL-3-inducible phenotypic subsets of basophils with distinct functional characteristics; 2) the first direct evidence for human basophil expression of the thymic stromal lymphopoietin receptor (TSLPR) and signaling in response to TSLP, which is regulated by IL-3 and IL-33; and 3) evidence for basophil "functional tolerance' regulated by IL-3. This proposal will investigate the central hypothesis that targeting IL-3 activation of basophils is an effective strategy for treatin basophil-mediated allergic diseases. Studies will use human basophils from healthy controls and patients with allergic diseases, as well as murine basophils from IL-3 deficient and control mice, and state-of-the-art cellular and molecular techniques. The central hypothesis will be investigated by testing the following four corollary hypotheses: Aim 1: Investigate the hypothesis that in the absence of IL-3, basophils are in a state of "functional tolerance", and that IL-3 activation of basophils breaks "functional tolerance" and results in heterogeneous subpopulations which may be either in sequential states of activation or stochastically distinct subpopulations; Aim 2: Investigate the hypothesis that IL-3 activated basophils respond to TSLP and acquire a functional phenotype that is polarized for inducing Th2 immune responses; Aim 3: Investigate the hypothesis that the IL-3 activation state of basophils determines the sensitivity o basophil activation testing for assessment of clinical atopy versus "functional tolerance"; and Aim 4: Investigate the hypothesis that antagonism, or lack, of IL-3 will result in basophil "functional tolerance" in [a murine model of atopy and a novel in vitro human model of atopy.] These studies have the potential to delineate the mechanisms by which basophils are activated for distinct effector functions, lead to novel assays for clinical evaluation of basophil activatio, and provide proof-of- concept for potentially targeting IL-3 as a novel treatment of allergic disorders.
DESCRIPTION (provided by applicant): The overall goal of this laboratory over the past 20 years has been the elucidation of mechanisms regulating allergic inflammation and thereby identification of novel targets for treating allergic diseases. This proposal will focus on mechanisms regulating human basophil activation and effector function in allergic diseases. Basophils are the least abundant granulocytes in the circulation, and only recently has evidence demonstrated that basophils have potent effector functions that bridge innate and adaptive immunity and contribute to the pathogenesis of both allergic and autoimmune diseases. Preliminary studies demonstrate that IL-3 is a key cytokine for polarizing basophils for effector functions that include degranulation in response to FcεR1 crosslinking, regulation of cell surface molecule expression, cytokine expression, and immune modulation. Key preliminary findings include: 1) detailed analysis of IL-3 activation of human basophils that demonstrates IL-3-inducible phenotypic subsets of basophils with distinct functional characteristics; 2) the first direct evidence for human basophil expression of the thymic stromal lymphopoietin receptor (TSLPR) and signaling in response to TSLP, which is regulated by IL-3 and IL-33; and 3) evidence for basophil "functional tolerance' regulated by IL-3. This proposal will investigate the central hypothesis that targeting IL-3 activation of basophils is an effective strategy for treatin basophil-mediated allergic diseases. Studies will use human basophils from healthy controls and patients with allergic diseases, as well as murine basophils from IL-3 deficient and control mice, and state-of-the-art cellular and molecular techniques. The central hypothesis will be investigated by testing the following four corollary hypotheses: Aim 1: Investigate the hypothesis that in the absence of IL-3, basophils are in a state of "functional tolerance", and that IL-3 activation of basophils breaks "functional tolerance" and results in heterogeneous subpopulations which may be either in sequential states of activation or stochastically distinct subpopulations; Aim 2: Investigate the hypothesis that IL-3 activated basophils respond to TSLP and acquire a functional phenotype that is polarized for inducing Th2 immune responses; Aim 3: Investigate the hypothesis that the IL-3 activation state of basophils determines the sensitivity o basophil activation testing for assessment of clinical atopy versus "functional tolerance"; and Aim 4: Investigate the hypothesis that antagonism, or lack, of IL-3 will result in basophil "functional tolerance" in [a murine model of atopy and a novel in vitro human model of atopy.] These studies have the potential to delineate the mechanisms by which basophils are activated for distinct effector functions, lead to novel assays for clinical evaluation of basophil activatio, and provide proof-of- concept for potentially targeting IL-3 as a novel treatment of allergic disorders.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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David P Huston其他文献

Finding new mineral prospects with HYMAP : early results from a hyperspectral remote-sensing case study in the west Pilbara
使用 HYMAP 寻找新的矿产前景:皮尔巴拉西部高光谱遥感案例研究的早期结果
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    0
  • 作者:
    P. Bierwirth;R. Blewett;David P Huston
  • 通讯作者:
    David P Huston

David P Huston的其他文献

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{{ truncateString('David P Huston', 18)}}的其他基金

Mechanisms of Human Basophil-Mediated Allergic Inflammation
人类嗜碱性粒细胞介导的过敏性炎症的机制
  • 批准号:
    8966613
  • 财政年份:
    2013
  • 资助金额:
    $ 40.36万
  • 项目类别:
Mechanisms of Human Basophil-Mediated Allergic Inflammation
人类嗜碱性粒细胞介导的过敏性炎症的机制
  • 批准号:
    8514186
  • 财政年份:
    2012
  • 资助金额:
    $ 40.36万
  • 项目类别:
Clinical Core
临床核心
  • 批准号:
    7149938
  • 财政年份:
    2006
  • 资助金额:
    $ 40.36万
  • 项目类别:
Regulation of TSLP Expression
TSLP 表达的调控
  • 批准号:
    7149928
  • 财政年份:
    2006
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    6835111
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    7191565
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    7007839
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    6571682
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    6694074
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:
Immunology Physician Scientist Training Grant
免疫学医师科学家培训补助金
  • 批准号:
    7008186
  • 财政年份:
    2003
  • 资助金额:
    $ 40.36万
  • 项目类别:

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