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制中发挥着重要作用。淋巴细胞产生的细胞因子失调导致单基因突变影响多个器官的嗜酸性粒细胞增多，为定义健康和疾病中的嗜酸性粒细胞提供了一个独特且有价值的模型。自发性、常染色体、隐性、慢性增殖性皮炎小鼠突变（基因符号：cpdm）就是这样一个模型。 cpdm 基因座定位于小鼠 15 号染色体的中部。纯合子 (cpdm/cpdm) 显示出与嗜酸性粒细胞、肥大细胞和 MHC II+ 细胞浸润相关的显着、进行性表皮增殖。皮肤和其他器官中的嗜酸性粒细胞增多伴有IL12分泌缺陷和淋巴器官发育异常。候选基因已被鉴定，并将对这些基因进行核苷酸变化测序。测序优先级将基于使用定量 RT PCR 方法表达水平的变化。基于外源重组IL12治疗后cpdm皮肤病的复杂表型、功能测定和解决，我们假设cpdm的功能包括但不限于调节IL12的产生。我们假设这种缺陷导致的细胞因子失调会增加 Th2 细胞因子的产生（IL4、IL5、ILl3 和 GMCSF），导致血液和组织嗜酸性粒细胞增多以及嗜酸性粒细胞诱导的组织损伤。对嗜酸粒细胞性皮炎机制的研究将首先通过 cpdm/cpdm 小鼠与缺乏 IL12b、llAra 或 IL5 的小鼠杂交来关注这一潜在途径。由于 cpdm/cpdm 小鼠中除皮肤外的许多器官都受到影响，我们相信，定义嗜酸性皮肤病的遗传学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粒细胞疾病。