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Molecular Mechanisms of lon Channels in T Lymphocytes

Molecular Mechanisms of lon Channels in T Lymphocytes
T淋巴细胞lon通道的分子机制
批准号:
10375085
负责人:
MICHAEL D CAHALAN
金额:
$4.78万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-04-01 至 2023-05-31

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英文摘要
Project Summary The overall objective of this renewal proposal is to better understand how Orai1 channels function in T cells at the molecular, subcellular, and cellular levels. Orai proteins are a novel class of Ca2+ channels in the plasma membrane (PM). They are activated by STIM proteins in the ER, with which they colocalize in puncta at ER-PM junctions following depletion of Ca2+ in the ER lumen. Despite the importance of Orai1 as a potential therapeutic target in T cells, crucial questions remain at single channel, puncta and cellular levels. In large part this is because single-channel recording with the patch-clamp technique cannot be applied to Orai1 or other Orai channels, which have exceptionally low conductance, and because local signalling takes place in STIM1:Orai1 puncta. To circumvent these limitations, our proposal is predicated on our recent development of novel Ca2+- indicator fusion proteins; an Orai1-GCaMP6f channel-indicator that reports single-channel signals, and a ratiometric, red/green cytosolic Ca2+ indicator. Implemented in transgenic mice, these probes are revealing new and unanticipated local Ca2+ signalling events and the first chance to monitor endogenous Orai1 activity in native T cells. In conjunction with T cell-specific Orai1 knockout mice, we use these tools to investigate: 1) how Orai1 is activated at the single-molecule level; 2) how Orai1 channel activity varies in puncta and in native T cells; and 3) how local Ca2+ signals modulate T cell motility during immune surveillance in the lymph node.
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Cellular and Molecular Mechanisms of Regulatory T Cells in EAE
  • 批准号:
    9301460
  • 项目类别:
  • 资助金额:
    $49.89万
  • 财政年份:
    2016
  • 负责人:
    MICHAEL D CAHALAN
  • 依托单位:
A Transgenic Mouse Line to Map Cell-Type Specific Calcium Signals In Vivo
  • 批准号:
    9001251
  • 项目类别:
  • 资助金额:
    $23.18万
  • 财政年份:
    2015
  • 负责人:
    MICHAEL D CAHALAN
  • 依托单位:
Immunology Research Training Program
  • 批准号:
    8486365
  • 项目类别:
  • 资助金额:
    $11.25万
  • 财政年份:
    2005
  • 负责人:
    MICHAEL D CAHALAN
  • 依托单位:
CORE--OPTICAL BIOLOGY FACILITY
  • 批准号:
    6336413
  • 项目类别:
  • 资助金额:
    $22.95万
  • 财政年份:
    2000
  • 负责人:
    MICHAEL D CAHALAN
  • 依托单位:
海外基金