Effects of insulin-dependent diabetes resistance alleles on CD8 tolerance in NOD

胰岛素依赖性糖尿病抵抗等位基因对 NOD 中 CD8 耐受性的影响

• 批准号: 7134119
• 负责人: LINDA A SHERMAN
• 金额: $ 72.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134119
• 关键词: alleles; genes; insulin dependent diabetes mellitus

DESCRIPTION (provided by applicant): NOD mice spontaneously develop Type 1 Diabetes (T1D) due to a loss of T cell tolerance to islet antigens. Congenic strains of NOD mice that are highly protected from the occurrence of T1D, because they have multiple resistance alleles situated on two chromosomes (ldd3/5 mice) or 3 linked resistance alleles on a single chromosome (Idd9), do not harbor high-avidity, islet-specific CDS T cells. In order to delineate the mechanism by which CDS tolerance is restored, we will trace the path of naive, islet-specific CDS cells in situations where resistance alleles at multiple or single Idd loci are expressed only in particular cell types. This will provide an assay that will identify the cell(s) that must express specific protective Idd genes to achieve CDS tolerance. We will then correlate gene expression of candidate Idd genes within the relevant cell populations obtained from NOD or congenic mice with the functional consequences that relate to protection from autoimmunity. Although four of the subregions, Idd3, Idd5.1, Idd5.2 and Idd9.3 are relatively well-characterized and the likely molecular basis of disease susceptibility is known in each case, Idd5.3, Idd9.2, and Idd9.1 require further efforts to positionally clone the Idd genes. Relevance: The occurrence of T1D in humans and mice has been mapped to a number of genetic susceptibility loci that prevent T cell tolerance to islet antigens. By elucidating naturally occurring mechanisms that restore such tolerance (as defined by Idd genes that prevent disease), we will better understand the etiology of the disease and also identify targets for interventions that can be used to prevent T1D.

描述（由申请人提供）： 由于 T 细胞对胰岛抗原的耐受性丧失，NOD 小鼠自发患上 1 型糖尿病 (T1D)。 NOD 小鼠的同系品系受到高度保护，免受 T1D 的发生，因为它们在两条染色体上有多个耐药等位基因（ldd3/5 小鼠）或在一条染色体上有 3 个连锁耐药等位基因（Idd9），但它们不含有高亲和力、胰岛特异性 CDS T 细胞。为了描述 CDS 耐受性恢复的机制，我们将在多个或单个 Idd 基因座的抗性等位基因仅在特定细胞类型中表达的情况下追踪幼稚的胰岛特异性 CDS 细胞的路径。这将提供一种检测方法，用于鉴定必须表达特定保护性 Idd 基因以实现 CDS 耐受性的细胞。然后，我们将从 NOD 或同源小鼠获得的相关细胞群中候选 Idd 基因的基因表达与与自身免疫保护相关的功能后果相关联。尽管四个亚区 Idd3、Idd5.1、Idd5.2 和 Idd9.3 的特征相对较好，并且每种情况下疾病易感性的可能分子基础都是已知的，但 Idd5.3、Idd9.2 和 Idd9.1 需要进一步努力来定位克隆 Idd 基因。相关性：人类和小鼠中 T1D 的发生已被定位到许多阻止 T 细胞对胰岛抗原耐受的遗传易感性位点。通过阐明恢复这种耐受性的自然发生机制（由预防疾病的 Idd 基因定义），我们将更好地了解该疾病的病因，并确定可用于预防 T1D 的干预措施的目标。