A Macrophage Cation Channel in Prevention and Recovery from Inflammatory Injury

巨噬细胞阳离子通道在炎症损伤预防和恢复中的作用

基本信息

  • 批准号:
    9519646
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-10-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Existing therapies for autoimmune and inflammatory diseases have minimal effects on resolution and recovery from chronic injury. There is also a fundamental gap in understanding how macrophages regulate cellular phenotype to mediate either injury or repair. The long-term goal is to develop treatments that prevent and reverse chronic inflammatory injury. Using a combination of cellular, genomic, proteomic and in vivo approaches, a novel splice variant of the human sodium channel gene, SCN5A, has been identified as a central regulator of anti-inflammatory macrophage signaling. This splice variant encodes a novel, endosomal cation channel that couples intracellular calcium flux to downstream signaling and gene transcription. Because this splice variant is not expressed in mice, a transgenic knock-in model, the C57BL6cfms-hSCN5A mouse, was developed to study its in vivo function in macrophages. Transfer of bone marrow derived macrophages from these mice mediates clinical recovery in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The objective of this study is to characterize the SCN5A signaling network in macrophages and determine how it regulates clinical recovery in the EAE model of chronic inflammatory disease. The central hypothesis is that persistent expression of SCN5A in macrophages initiates and maintains a cellular phenotype that enhances recovery from inflammatory injury. The rationale for this study is that understanding this mechanism will lead to innovative approaches to prevent and treat chronic inflammatory disease. The hypothesis will be tested in two specific aims: 1. Determine how the SCN5A variant cation channel regulates macrophage phenotype. 2. Analyze how SCN5A+ macrophages mediate recovery during EAE. Based on preliminary data, the working model is that endosomal channel activity mediates short-term biochemical signaling and long-term gene expression patterns that determine and maintain cellular phenotype. In Aim 1, channel-dependent regulation of cytosolic calcium, cyclic AMP, and activating transcription factor 2 (ATF2) pathways will be examined. The experimental approaches will include a combination of existing biochemical, imaging and molecular techniques in mouse and human primary macrophages. In Aim 2, the EAE model will be utilized to assess this pathway in vivo and determine how SCN5A+ macrophages mediate recovery from inflammatory injury. In vivo gene and protein expression will be analyzed and correlated with in vitro assessment of SCN5A regulation of macrophage vesicular secretion and intercellular communication. The proposed work is innovative because it represents a new approach to regulate macrophage function and treat chronic inflammatory disease. It is significant because promotion of recovery in MS and other chronic inflammatory diseases represents an unmet therapeutic need.
描述(由申请人提供):

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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MICHAEL D CARRITHERS其他文献

MICHAEL D CARRITHERS的其他文献

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{{ truncateString('MICHAEL D CARRITHERS', 18)}}的其他基金

Human Macrophage Sodium Channels: Novel Targets for Inflammatory Diseases
人巨噬细胞钠通道:炎症性疾病的新靶点
  • 批准号:
    8196324
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
A Macrophage Cation Channel in Prevention and Recovery from Inflammatory Injury
巨噬细胞阳离子通道在炎症损伤预防和恢复中的作用
  • 批准号:
    9259894
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Human Macrophage Sodium Channels: Novel Targets for Inflammatory Diseases
人巨噬细胞钠通道:炎症性疾病的新靶点
  • 批准号:
    8391532
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells
通过人骨髓细胞中新型先天免疫信号通路调节中枢神经系统炎症性疾病的易感性和严重程度
  • 批准号:
    9888928
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells
通过人骨髓细胞中新型先天免疫信号通路调节中枢神经系统炎症性疾病的易感性和严重程度
  • 批准号:
    10057220
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Human Macrophage Sodium Channels: Novel Targets for Inflammatory Diseases
人巨噬细胞钠通道:炎症性疾病的新靶点
  • 批准号:
    8597334
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells
通过人骨髓细胞中新型先天免疫信号通路调节中枢神经系统炎症性疾病的易感性和严重程度
  • 批准号:
    10412923
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells
通过人骨髓细胞中新型先天免疫信号通路调节中枢神经系统炎症性疾病的易感性和严重程度
  • 批准号:
    10516089
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Human Macrophage Sodium Channels: Novel Targets for Inflammatory Diseases
人巨噬细胞钠通道:炎症性疾病的新靶点
  • 批准号:
    7928446
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
A Macrophage Cation Channel in Prevention and Recovery from Inflammatory Injury
巨噬细胞阳离子通道在炎症损伤预防和恢复中的作用
  • 批准号:
    8733411
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:

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