Role of the Fragilis Proteins in the Immune Response

脆弱蛋白在免疫反应中的作用

• 批准号: 6804271
• 负责人: John Weis
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804271
• 关键词: biological signal transduction; cell type; gene expression; genetic manipulation; genetically modified animals; immune response; immunogenetics; laboratory mouse; macrophage; membrane proteins; phenotype; protein structure function; ubiquitin

DESCRIPTION (provided by applicant): The fragilis gene family represents a relatively unknown group of interferon beta inducible genes/gene products who have been implicated in the down modulation of the immune response. The human and mouse genomes possess 3 to 5 copies of members of this family, respectively. The most well known is the human protein Leu-13 that has been described as a constituent of a number of signal transduction complexes on T cells, B cells and monocytes. The best known of these complexes is the complement receptor CR2 complex on human B cells. Virtually no studies have been carried out on how this protein can influence such signaling although it is clear it does play a down modulatory role. We propose to utilize the unique format of the R21 application to test a novel hypothesis: that the fragilis proteins are members of a ubiquitin modification pathway. Specifically we propose that the fragilis proteins function within the membrane to tag key regulatory proteins, either cell surface proteins or membrane associated signal transduction proteins, with ubiquitin (or ubiquitin family members). This tag can then act to either modify the activity of these signaling molecules or target them for destruction via the proteosome pathway. We will couple this hypothesis with defining the types of membrane regulatory complexes that the fragilis proteins are part of, and to characterize the phenotype of an engineered knockout animal that is lacking one of the murine fragilis genes, fragilis5, that is preferentially expressed in macrophages. By combining the data obtained from these approaches we hope to have described a specific set of functions for the fragilis proteins as well as to have defined the cell types and specific signal transduction pathways that they modify. These proteins represent yet another bridge between the molecules that function within the antigen specific response (B cell receptor, T cell receptor, etc) and those of the innate immune response.

描述（由申请人提供）：Fragilis基因家族代表了一组相对未知的干扰素β型基因/基因产物，这些基因/基因产物与免疫反应的下降调节有关。人和小鼠基因组分别具有该家族成员的3到5份。最著名的是人类蛋白LEU-13，它被描述为T细胞，B细胞和单核细胞上许多信号转导复合物的组成。这些复合物中最著名的是人B细胞上的补体受体CR2复合物。几乎没有关于这种蛋白质如何影响这种信号传导的研究，尽管显然它确实起着调节作用。我们建议利用R21应用的唯一格式来检验一种新的假设：脆弱的蛋白是泛素修饰途径的成员。具体而言，我们建议脆弱的蛋白质在膜内发挥作用，以标记关键调节蛋白，无论是细胞表面蛋白或膜相关的信号转导蛋白，带有泛素（或泛素家族成员）。然后，该标签可以作用以修改这些信号分子的活性，或者通过蛋白质体途径靶向破坏它们。我们将将这一假设与定义脆弱蛋白是一部分的膜调节复合物的类型，并表征缺少一种鼠叶状基因fragilis5的工程敲除动物的表型，该基因在巨噬细胞中优先表达。通过结合从这些方法获得的数据，我们希望已经描述了Fragilis蛋白的一组特定功能，并定义了它们修改的细胞类型和特定的信号转导途径。这些蛋白质代表了在抗原特异性反应（B细胞受体，T细胞受体等）中起作用的分子与先天免疫反应的另一个桥梁。