GENETIC AND MOLECULAR BASIS OF FAMILIAL COLD URTICARIA

该项目的长期目标是本地化和 家族性寒冷性荨麻疹致病基因的鉴定。 家族性寒冷性麻疹是免疫系统的一个很好的例子 对环境中的物理刺激的反应。这种情况 提供了一个新的机会来研究潜在的机制 从分子遗传学的角度看炎症，因为它 经典常染色体显性遗传模式。这是独一无二的 一个受影响的大家庭积极参与拟议的 在离加州大学圣迭戈分校很近的地方进行研究，那里有必要的资源 进行分子遗传学研究。有很多炎症性的 由身体刺激引起的疾病，它们可能有共同之处 其他炎症性疾病的机制。因此，这个基因 家族性寒冷性荨麻疹的研究可能会增加对它的认识 调控炎症反应的分子机制。 最终，这将导致改善对家族性感冒的治疗 荨麻疹和其他炎症性疾病。 本项目的具体目标是：(1)进行系统的 利用短串联重复序列多态性对全基因组的研究 标记最初间隔20厘米，后来间隔10厘米，如果 必要的；(2)使用联动进行多点联动分析 程序以识别LOD分数大于+2和 在更精细地映射这些区域以识别具有细节的区域之后 分数大于+3且大小约为1-2厘米；(3)至 使用多个克隆系统组合开发连续的物理地图 以及染色体行走和STS内容定位等技术； 使用技术在有限区域内识别候选基因 如cDNAs选择和外显子捕获；以及(5)筛选这些基因 最初使用脉冲场凝胶电泳法进行大体重排 然后使用单链进行更细微的DNA改变 构象多态分析。这些目标的实现 将导致确定导致家族性感冒的基因 这将最终导致对麻疹的理解 对物理刺激的炎症反应的机制。

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.