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起主要作用。由淋巴细胞产生的细胞因子的失调导致嗜酸性粒细胞增多症通过单个基因突变影响多个器官，这为定义健康和疾病中的嗜酸性粒细胞提供了独特且有价值的模型。自发性、常染色体、隐性、慢性增生性皮炎突变小鼠（基因符号：cpdm）就是这样一种模型。cpdm基因定位于小鼠15号染色体的中部。纯合子（cpdm/cpdm）表现出明显的、进行性的表皮增生，伴有嗜酸性粒细胞、肥大细胞和MHC II+细胞浸润。皮肤和其它器官中的嗜酸性粒细胞增多症伴有IL 12分泌缺陷和淋巴器官发育异常。候选基因已经确定，这些将被测序的核苷酸变化。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、功能测定和外源性重组IL 12治疗后cpdm皮肤病的消退，我们假设cpdm的功能包括但不限于调节IL 12的产生。我们假设由该缺陷引起的细胞因子的失调增加了Th 2细胞因子（IL 4、IL 5、IL 13和GMCSF）的产生，引起血液和组织嗜酸性粒细胞增多和嗜酸性粒细胞诱导的组织损伤。对嗜酸性皮炎机制的研究最初将通过产生cpdm/cpdm小鼠与缺乏IL 12 b、IlAra或IL 5的小鼠的杂交来集中于该潜在途径。由于cpdm/cpdm小鼠除了皮肤外，还有许多器官受到影响，我们相信，确定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疾病。