Genetic Control of Autoimmune Exocrinopathy in NOD Mice

NOD 小鼠自身免疫性外分泌病的遗传控制

• 批准号: 6873700
• 负责人: AMMON B PECK
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873700
• 关键词: NOD mouse; SDS polyacrylamide gel electrophoresis; Sjogren' s syndrome; acinar cell; animal genetic material tag; autoantibody; biotechnology; confocal scanning microscopy; disease /disorder etiology; exocrine glands; flow cytometry; gene expression; gene interaction; genetic library; genetic mapping; genetic susceptibility; genetically modified animals; high throughput technology; microarray technology; molecular cloning; nucleic acid sequence; pathologic process; polymerase chain reaction; southern blotting; subtraction hybridization; western blottings

DESCRIPTION (provided by applicant): Sjogren's syndrome, an autoimmune disease that is one of the leading causes of salivary gland inflammation and dysfunction, leads to severe dryness of the oral cavity. Dry mouth is thought to result from a genetic predisposition that, in association with environmental stimuli, results in a chronic immune attack against specific (auto)-antigens expressed in salivary gland tissue. Although HLA inheritance has been recognized as an important risk factor for most autoimmune diseases, as yet no HLA genotype has been identified as being associated with an increased risk for developing Sjogren's syndrome. Non-HLA genes also appear to contribute to the genetic predisposition in humans, but identification of non-HLA genes only complicates5ability to understand the genetic basis of Sjogren's syndrome. Animal models of autoimmune disease provide an excellent resource for identifying genetic pathways responsible for underlying pathogenesis. We have popularized the NOD mouse as a model for Sjogren's syndrome as this mouse develops progressive lymphocytic infiltration, cytokine and autoantibody production in the exocrine glands concomitant with decreased exocrine gland secretions. Using the multiple congenic strains of NOD now available, two NOD-derived loci, designated Aec1 and Aec2 (autoimmune exocrinopathy genetic regions 1 and 2) containing insulin dependent diabetic loci Idd3 on chromosome 3 and Idd5 on chromosome 1, respectively, have been identified. These two intervals appear to act in an additive and hierarchical manner to control the epithelial cell pathology, subsequent accumulation of lymphocytic infiltrates, and the eventual loss of secretory function of the salivary (and lachrymal) glands in the NOD mouse. We have successfully developed the C57BL/6.NOD- Aecl Aec2 mouse which recapitulates the complete disease phenotype observed in the parental NOD mouse. To further map the chromosomal intervals, we propose to generate recombinant inbred (RI) strains of the C57BL/6.NOD- Aecl Aec2 mouse. For Specific Aim t, aset of RI strains of C57BL/6.NOD- Aecl Aec2 mice will be generated to fine-map the Aecf and Aec2 genetic regions to identify specific intervals associated with the development of autoimmune exocrinopathy in the NOD mouse. For Specific Aim 2, cDNA microarray technology will be used to identify candidate genes within these intervals responsible for immune and non-immune components resulting in autoimmune exocrinopathy by comparing expression levels of transcripts from disease-susceptible versus non-susceptible RI mice. Results from these studies will provide insight into the genetic mechanism(s) underlying the pathogenesis of Sjogren's syndrome important to the long-term goal of developing targeted preventive or ready intervention strategies.

描述（由申请人提供）：干燥综合征是一种自身免疫性疾病，是唾液腺炎症和功能障碍的主要原因之一，会导致口腔严重干燥。口干被认为是由遗传倾向引起的，这种遗传倾向与环境刺激有关，导致对唾液腺组织中表达的特定（自身）抗原的慢性免疫攻击。尽管HLA遗传已被认为是大多数自身免疫性疾病的重要危险因素，但迄今为止尚未发现HLA基因型与患干燥综合征的风险增加相关。非 HLA 基因似乎也与人类的遗传倾向有关，但非 HLA 基因的鉴定只会使了解干燥综合征的遗传基础变得复杂。自身免疫性疾病的动物模型为识别导致潜在发病机制的遗传途径提供了极好的资源。我们已推广 NOD 小鼠作为干燥综合征的模型，因为该小鼠在外分泌腺中出现进行性淋巴细胞浸润、细胞因子和自身抗体的产生，同时外分泌腺分泌减少。利用现有的多个同系 NOD 菌株，已鉴定出两个 NOD 衍生基因座，命名为 Aec1 和 Aec2（自身免疫性外分泌病遗传区 1 和 2），分别包含 3 号染色体上的胰岛素依赖性糖尿病基因座 Idd3 和 1 号染色体上的 Idd5。这两个时间间隔似乎以累加和分层的方式起作用，以控制 NOD 小鼠的上皮细胞病理、随后淋巴细胞浸润的积累以及唾液（和泪腺）腺的分泌功能的最终丧失。我们已经成功开发了 C57BL/6.NOD-Aecl Aec2 小鼠，它概括了在亲代 NOD 小鼠中观察到的完整疾病表型。为了进一步绘制染色体间隔图，我们建议生成 C57BL/6.NOD-Aecl Aec2 小鼠的重组近交 (RI) 品系。对于特定目标，将生成一组 C57BL/6.NOD-Aecl Aec2 小鼠的 RI 品系，以精细绘制 Aecf 和 A​​ec2 遗传区域，以确定与 NOD 小鼠中自身免疫性外分泌病的发展相关的特定区间。对于具体目标 2，cDNA 微阵列技术将用于通过比较疾病敏感与不敏感 RI 小鼠的转录物表达水平来识别这些区间内负责导致自身免疫性外分泌病的免疫和非免疫成分的候选基因。这些研究的结果将深入了解干燥综合征发病机制的遗传机制，这对于制定有针对性的预防或现成干预策略的长期目标非常重要。