GENETIC AND MOLECULAR BASIS OF FAMILIAL COLD URTICARIA

家族性寒冷性荨麻疹的遗传和分子基础

• 批准号: 2453645
• 负责人: HAROLD M HOFFMAN
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2453645
• 关键词: autosomal dominant trait; chromosome walking; clinical research; cold temperature; family genetics; gene expression; gene rearrangement; genetic mapping; genetic polymorphism; human subject; inflammation; linkage mapping; molecular biology; molecular cloning; molecular genetics; pulsed field gel electrophoresis; sequence tagged sites; single strand conformation polymorphism; urticaria

The long term objective of this project is the localization and identification of the gene responsible for familial cold urticaria. Familial cold urticaria is an excellent example of the immune system's response to physical stimuli in the environment. This condition provides a novel opportunity to study underlying mechanisms of inflammation from a molecular genetic perspective because of its classical autosomal dominant inheritance pattern. It is unique to have a large affected family motivated to participate in the proposed research in close proximity to UCSD which has the resources necessary to perform molecular genetic studies. There are many inflammatory diseases induced by physical stimuli and they may share common mechanisms with other inflammatory disorders. Therefore this genetic study of familial cold urticaria will likely increase the understanding of the molecular mechanisms regulating inflammatory responses. Ultimately this will lead to improved treatment of familial cold urticaria and other inflammatory disorders. The specific goals of this project are: (1) to conduct a systematic survey of the entire genome using short tandem repeat polymorphisms with markers spaced at 20 centiMorgans (cM) initially and later at 10 cM if necessary; (2) to perform multi-point linkage analysis using the LINKAGE program to identify regions with a lod score greater than plus 2 and after finer mapping of these regions to identify regions with a lod score greater than plus 3 and an approximate size of 1-2 cM; (3) to develop a contiguous physical map using a combination of cloning systems and techniques such as chromosome walking and STS content mapping; (4) to identify candidate genes within the limited region using techniques such as cDNA selection and exon trapping; and (5) to screen these genes initially for gross rearrangements using pulse field gel electrophoresis and then for more subtle DNA alterations using single strand conformational polymorphism analysis. The achievement of these goals will result in identification of the gene responsible for familial cold urticaria which will ultimately lead to an understanding of the mechanism of the inflammatory response to a physical stimulus.

该项目的长期目标是本地化， 确定基因负责家族性寒冷荨麻疹。 家族性寒冷性荨麻疹是免疫系统 对环境中物理刺激的反应。 这种情况 提供了一个新的机会，研究潜在的机制， 从分子遗传学的角度来看， 典型的常染色体显性遗传模式。 它是独一无二的， 一个受影响的大家庭积极参与拟议的 研究靠近UCSD，有必要的资源 进行分子遗传学研究 有许多炎症 由物理刺激引起的疾病，它们可能有共同的 与其他炎症性疾病的机制。 因此，这种基因 对家族性寒冷性荨麻疹的研究可能会增加对 调节炎症反应的分子机制 最终，这将导致改善家庭感冒的治疗 荨麻疹和其他炎性疾病。 本项目的具体目标是：（1）进行系统的 使用短串联重复序列多态性的全基因组调查， 标记间隔最初为20厘摩（cM），随后为10 cM，如果 （2）使用LINKAGE进行多点连锁分析 识别LOD得分大于+2的区域的程序， 在对这些区域进行更精细的映射以识别具有LOD的区域之后 得分大于+3，大小约为1-2 cM;（3）至 使用克隆系统的组合开发连续的物理图 以及染色体步移和STS内容映射等技术;（4） 在有限区域内识别候选基因 如cDNA选择和外显子捕获;和（5）筛选这些基因 最初使用脉冲场凝胶电泳进行总重排 然后利用单链DNA进行更细微的DNA改变， 构象多态性分析 实现这些目标 将鉴定出导致家族性感冒的基因 荨麻疹，这将最终导致了解的 对物理刺激的炎症反应机制。