Characterization of new Ca2+ channels that underpin immunological decision making

支持免疫决策的新 Ca2+ 通道的表征

• 批准号: 8462897
• 负责人: JEAN-PIERRE M KINET
• 金额: $ 40.89万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462897
• 关键词: Apoptosis; Asthma; Autoimmunity; Brain; CD4 Positive T Lymphocytes; Calcium ion; Cardiac; Cell Differentiation process; Cell physiology; Cells; Data; Decision Making; Defect; Development; Disease; Event; Exocytosis; Goals; Helper-Inducer T-Lymphocyte; Homologous Gene; Hypersensitivity; Immune; Immune System Diseases; Immune System Part; Immune response; Immune system; Infection; Ion Channel; Knowledge; Lead; Lymphocyte; Mediating; Membrane Potentials; Modality; Molecular; Nature; Neurons; Outcome; Pathogenesis; Pattern; Play; Population; Positioning Attribute; Production; Research; Rest; Role; Shapes; Signal Pathway; Signal Transduction; Surface; T cell differentiation; T-Lymphocyte; Th1 Cells; Up-Regulation; Variant; base; cell motility; cytokine; design; experience; fighting; in vivo Model; innovation; interest; novel; nuclear factor of activated T-cells, cytoplasmic 1 protein; nuclear factor of activated T-cells, cytoplasmic 2 protein; pre-clinical; prevent; programs; protein expression; research study; response; sulfated glycoprotein 2; therapeutic target

DESCRIPTION (provided by applicant): CD4+ T cells play a fundamental role in orchestrating immune responses. Aberrant T lymphocyte signaling underlies the pathogenesis of numerous diseases including autoimmunity, asthma and allergy. Therefore, unraveling the signaling pathways that govern T helper lineage commitment and function is crucial toward gaining a better understanding the molecular basis underpinning these disease states. An increase in intracellular calcium ion concentration ([Ca2+]i) is an essential signal that regulates numerous T cellular functions. Variations in both the amplitude and duration of Ca2+ signaling patterns differentially regulate transcriptional programs in lymphocytes, yet little is understood as to which Ca2+ channels mediate these signals and consequently control T cell differentiation. The T-type channel CaV3.1, best known for its role in brain and cardiac function, is expressed on nave T lymphocytes, regulates a Ca2+ entry at resting membrane potentials and is dramatically up-regulated during Th2 differentiation. Genetically deleting CaV3.1 in T lymphocytes decreases baseline Ca2+ influx, has no impact on store-operated Ca2+ entry (SOCE) and skews the cells towards Th1 differentiation. Moreover, deleting CaV3.1 prevents Gata-3 expression while favoring T-bet expression. These observations provide evidence that CaV3.1 T-type Ca2+ channels regulates Th1/Th2 polarization and suggest a surprising role for CaV3.1- mediated Ca2+ entry in T lymphocyte differentiation. The objective of this application is to fully characterize the function of CaV3.1 as it relates to Th lymphocyte differentiation and function. We propose experiments to define the requirement of CaV3.1 in Th differentiation (Aim 1), dissect the signaling pathways that CaV3.1 regulates (Aim 2) and determine if it regulates Th2 responses that underlie common immune diseases such as asthma and various allergies (Aim 3). We anticipate that the outcomes of the proposed experiments will greatly enhance our understanding of the molecular nature of Ca2+ signaling events required to shape T cell differentiation.

描述（由申请人提供）：CD 4 + T细胞在协调免疫应答中发挥重要作用。异常的T淋巴细胞信号传导是许多疾病的发病机制的基础，包括自身免疫、哮喘和过敏。因此，解开控制T辅助细胞谱系定型和功能的信号通路对于更好地理解这些疾病状态的分子基础至关重要。细胞内钙离子浓度（[Ca 2 +]i）的增加是调节许多T细胞功能的重要信号。Ca 2+信号模式的幅度和持续时间的变化差异调节淋巴细胞中的转录程序，但很少有人知道哪些Ca 2+通道介导这些信号，从而控制T细胞分化。T型通道CaV3.1，最为人所知的是其在脑和心脏功能中的作用，在幼稚T淋巴细胞上表达，调节静息膜电位下的Ca 2+进入，并且在Th 2分化期间显著上调。在T淋巴细胞中基因缺失CaV3.1会降低基线Ca 2+内流，对钙池操作的Ca 2+内流（SOCE）没有影响，并使细胞向Th 1分化倾斜。此外，删除CaV 3.1阻止了加塔-3表达，同时有利于T-bet表达。这些观察结果提供了CaV3.1 T型Ca 2+通道调节Th 1/Th 2极化的证据，并表明CaV3.1介导的Ca 2+进入T淋巴细胞分化中的惊人作用。本申请的目的是充分表征CaV3.1的功能，因为它涉及Th淋巴细胞分化和功能。我们提出实验来定义CaV3.1在Th分化中的需求（目标1），剖析CaV3.1调节的信号通路（目标2），并确定它是否调节常见免疫疾病（如哮喘和各种过敏症）的Th 2应答（目标3）。我们预计，所提出的实验的结果将大大提高我们的理解所需的形状T细胞分化的Ca 2+信号事件的分子性质。