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: 6574886
• 负责人: AMMON B PECK
• 金额: $ 32.63万
• 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/6574886
• 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）：Sjogren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，导致口腔严重干燥。据认为，口干是由遗传易感性引起的，该遗传易感性与环境刺激相关，导致对唾液腺组织中表达的特定（自动）抗原的慢性免疫发作。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，但尚未确定HLA基因型与发展Sjogren综合征的风险增加有关。非HLA基因似乎也有助于人类的遗传易感性，但是非HLA基因的鉴定仅使人们能够理解Sjogren综合征的遗传基础。自身免疫性疾病的动物模型为识别负责潜在发病机理的遗传途径提供了极好的资源。我们已经将NOD小鼠推广为Sjogren综合征的模型，因为该小鼠在外分泌腺体中与外分泌腺体分泌减少的外分泌腺体中的进行性淋巴细胞浸润，细胞因子和自身抗体的产生。使用现在可用的多种先天性点头菌株，两个点头衍生的基因座，指定为AEC1和AEC2（自身免疫性外分泌病遗传区域1和2），其中含有胰岛素依赖性糖尿病依赖性糖尿病基因座IDD3，分别已鉴定在染色体1上的3和IDD5上。这两个间隔似乎以加性和分层的方式作用，以控制上皮细胞病理，随后的淋巴细胞浸润的积累以及NOD小鼠中唾液（和lachrymal）腺体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，该小鼠概括了在父母点头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，我们建议生成C57BL/6.NOD-AECL AEC2小鼠的重组近交（RI）菌株。对于特定的目标t，将生成C57BL/6. NOD-AECL AEC2小鼠的RI菌株的ASET，以量化AECF和AEC2遗传区域，以识别与NOD小鼠中自身免疫性外分病的发展相关的特定间隔。对于特定的目标2，将使用cDNA微阵列技术在这些间隔内识别候选基因，从而通过比较来自疾病敏感的转录本的表达水平，从而导致自身免疫性外分泌病，从而导致自身免疫性外分泌病。这些研究的结果将提供对Sjogren综合征发病机理的遗传机制，对制定有针对性的预防或就绪干预策略的长期目标很重要。