Cpdm: Cloning a Gene That Regulates Eosinophil Function

Cpdm：克隆调节嗜酸性粒细胞功能的基因

• 批准号: 6947241
• 负责人: JOHN Paul SUNDBERG
• 金额: $ 32.76万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-08 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947241
• 关键词: antiantibody; bioinformatics; cytokine; dermatitis; eosinophil; gene expression; gene mutation; genetic regulation; helper T lymphocyte; histopathology; interleukin 12; keratinocyte; laboratory mouse; lymphocyte; nucleic acid sequence; phenotype; polymerase chain reaction

DESCRIPTION (provided by applicant): Eosinophils play a major role in the pathogenesis of a variety of human diseases. Dysregulation of cytokines produced by lymphocytes that result in eosinophilia affecting multiple organs by a single gene mutation provides a unique and valuable model to define eosinophils in health and disease. The spontaneous, autosomal, recessive, chronic proliferative dermatitis mouse mutation (gene symbol: cpdm) is such a model. The cpdm locus maps to the middle of mouse Chromosome 15. Homozygotes (cpdm/cpdm) show marked, progressive, epidermal proliferation associated with infiltration of eosinophils, mast cells, and MHC II+ cells. Eosinophilia in the skin and other organs is accompanied by a defect in the secretion of ILl2 and abnormalities in the development of lymphoid organs. Candidate genes have been identified and these will be sequenced for nucleotide changes. Sequencing priority will be based upon changes in expression levels using quantitative RT PCR methods. Based on the complex phenotype, functional assays, and resolution of the cpdm skin disease following exogenous recombinant ILl2 treatment, we postulate that the function of cpdm includes but is not limited to the regulation of ILl2 production. We hypothesize that dysregulation of cytokines resulting from this defect augments Th2 cytokine production (IL4, IL5, ILl3, and GMCSF) causing blood and tissue eosinophilia and eosinophil-induced tissue damage. Studies on the mechanism of eosinophilic dermatitis will initially focus on this potential pathway by generating crosses of cpdm/cpdm mice with mice lacking IL12b, llAra, or IL5. Since many organs in addition to the skin are affected in cpdm/cpdm mice, we believe that defining the genetics and mechanisms of eosinophilic skin disease will enable us to better understand eosinophilic diseases in the lung and other tissues.

描述（由申请人提供）： 嗜酸性粒细胞在多种人类疾病的发病机理中起主要作用。淋巴细胞产生的细胞因子的失调，导致嗜酸性粒细胞通过单个基因突变影响多个器官，这为定义健康和疾病中定义嗜酸性粒细胞的独特而有价值。自发，常染色体，隐性，慢性增生性皮炎小鼠突变（基因符号：CPDM）就是这样的模型。 CPDM基因座图至小鼠染色体15的中间。纯合子（CPDM/CPDM）显示出与嗜酸性粒细胞，肥大细胞和MHC II+细胞浸润有关的标志性，进行性表皮增殖。皮肤和其他器官中的嗜酸性粒细胞伴随着Ill2分泌和淋巴器官发育异常的缺陷。候选基因已被鉴定出来，这些基因将被测序以进行核苷酸变化。测序优先级将基于使用定量RT PCR方法的表达水平变化。基于复杂的表型，功能分析和外源性重组ILL2治疗后CPDM皮肤疾病的分辨率，我们假设CPDM的功能包括但不限于调节Ill2产生。我们假设由于这种缺陷而导致的细胞因子的失调增强了Th2细胞因子的产生（IL4，IL5，ILL3和GMCSF），从而导致血液和组织嗜酸性粒细胞增生和嗜酸性粒细胞诱导的组织损伤。关于嗜酸性粒细胞性皮炎机制的研究最初将通过缺乏IL12B，Llara或IL5的小鼠产生CPDM/CPDM小鼠的杂交来关注这一潜在途径。由于除了皮肤外，许多器官都受到CPDM/CPDM小鼠的影响，因此我们认为，定义嗜酸性皮肤疾病的遗传和机制将使我们能够更好地了解肺和其他组织中的嗜酸性疾病。