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Using Genomics to Understand Autoimmune Diabetes

Using Genomics to Understand Autoimmune Diabetes
利用基因组学了解自身免疫性糖尿病
批准号:
6637874
负责人:
JONATHAN David KATZ
金额:
$27.15万
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-06-01 至 2007-04-30

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中文摘要
翻译
描述(由申请人提供):非肥胖糖尿病(NOD)小鼠为1型糖尿病(T1DM)提供了极好的模型。多项证据表明 T1DM 是 Th1 自身免疫反应的结果。例如,我们小组和其他人的研究表明,胰岛反应性 Th1(产生干扰素 (IFN)-gamma)T 细胞会转移糖尿病,而胰岛反应性 Th2(产生白细胞介素 (IL)-4)T 细胞则不会。这些和其他数据支持 T1DM 发展与 Th1 反应相关的观点。然而,与其他器官特异性自身免疫性疾病一样,T1DM 的发病机制显然不仅仅涉及产生 IFN-γ 的淋巴细胞的发育。事实上,IFN-γ 和 IFN-γ 受体缺陷的 NOD 小鼠都会患上 T1DM。 因此,对 T1DM 的免疫发病机制建立更深入、更机制的理解至关重要。为此,我们利用胰岛特异性 T 细胞受体 (TCR) 转基因 NOD 小鼠亚系所表现出的疾病谱,利用功能基因组学技术分析体内疾病的分子进化。这些研究的一般假设是:(a) NOD 小鼠的糖尿病是一种 Th1 相关疾病; (b) NOD小鼠中的疾病表达不依赖于IFN-γ的表达或活性,IFN-γ是Th1反应的表面表型标志物; (c) 疾病和组织特异性基因表达的整体特征将有助于更全面地了解 NOD 小鼠糖尿病的发病机制。这些研究中正在测试的具体假设是,对分子发病机制进行仔细的功能基因组学方法将允许详细描述对于 NOD 小鼠疾病发病机制真正重要的 Th1 相关炎症反应的那些方面。为此,我们的目标是: 目标 1:建立一组有限且经过验证的基因,其表达模式可直接分期并预测 NOD 小鼠自发疾病进展的过程。 目标 2:阐明 IFN-γ 和 IFN-γ 受体缺陷型 NOD 小鼠在缺乏干扰素-γ 活性的情况下自发形成 T1DM 的遗传机制。 目标 3:建立胰岛反应性 Th1 和 Th2 T 细胞 NOD 受体中与疾病进展和抵抗相关的差异基因表达模式。
英文摘要
DESCRIPTION (provided by applicant): The non-obese diabetic (NOD) mouse provides an excellent model for e type 1 diabetes mellitus (T1DM). Several lines of evidence suggest that T1DM results from a Th1 autoimmune response. For example, studies by our group and others have shown that islet-reactive Th1 (interferon (IFN)-gamma producing) T cells transfer diabetes, while islet-reactive Th2 (interleukin (IL)-4 producing) T cells do not. These and other data support the notion that T1DM development correlates with a Th1 response. However, the pathogenesis of T1DM, like that of other organ-specific autoimmune diseases, clearly involves more than the development of IFN-gamma producing lymphocytes. Indeed, both IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop T1DM. Therefore, it is critical that a deeper, more mechanistic understanding of the immunopathogenesis of T1DM be established. To this end, we have taken advantage of the spectrum of disease exhibited by sub-lines of our islet-specific T cell receptor (TCR) transgenic NOD mice to analyze the molecular evolution of disease in vivo, using the technique of functional genomics. The general hypotheses underlying these studies are: (a) that diabetes in NOD mice is a Th1-associated disease; (b) that disease expression in the NOD mouse is not dependent upon the expression or activity of IFN-gamma, the superficial phenotype marker of a Th1 response; and (c) that global characterization of disease- and tissue-specific gene expression will allow for a more complete understanding of the pathogenesis of diabetes in the NOD mouse. The specific hypothesis being tested in these studies is that a careful, functional genomics approach to molecular pathogenesis will allow for the detailed delineation of those aspects of the Th1-associated inflammatory response that are truly essential for disease pathogenesis in the NOD mouse. To this end, we aim: Aim 1: To establish a limited and verified set of genes whose expression patterns directly stage and predict the course of spontaneous disease progression in NOD mice. Aim 2: To delineate the genetic mechanism by which IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop spontaneous T1DM in the absence of interferon-gamma activity. Aim 3: To establish the differential gene expression pattern associated with disease progression and resistance in NOD recipients of islet-reactive Th1 and Th2 T cells.
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Manipulating DNA Damage-response Signaling for the Treatment of Type 1 Diabetes
  • 批准号:
    10319938
  • 项目类别:
  • 资助金额:
    $44.68万
  • 财政年份:
    2019
  • 负责人:
    JONATHAN David KATZ
  • 依托单位:
Manipulating DNA Damage-response Signaling for the Treatment of Type 1 Diabetes
  • 批准号:
    10091310
  • 项目类别:
  • 资助金额:
    $44.68万
  • 财政年份:
    2019
  • 负责人:
    JONATHAN David KATZ
  • 依托单位:
Dissecting Dendritic Cell Function in Autoimmune Diabetes
  • 批准号:
    7741266
  • 项目类别:
  • 资助金额:
    $36.38万
  • 财政年份:
    2009
  • 负责人:
    JONATHAN David KATZ
  • 依托单位:
Dissecting Dendritic Cell Function in Autoimmune Diabetes
  • 批准号:
    8119440
  • 项目类别:
  • 资助金额:
    $32.62万
  • 财政年份:
    2009
  • 负责人:
    JONATHAN David KATZ
  • 依托单位:
海外基金