SPECIFIC INTEGRIN ALPHA 4 CYTOPLASMIC TAIL FUNCTIONS

描述（改编自申请人的摘要）： 整合素α 4亚基的结构域与其他α 链胞质结构域相对于粘着斑形成，和 这可以解释增加的细胞迁移，但减少的细胞迁移。 铺展、粘附强化、质膜硬度和PIP 4，5 合成. 首席研究员假设， α-4尾部的结构特征产生了它的专门的 与特定的生物化学协会协调， 信号通路 此外，主要研究者假设 α-4尾的这些独特特征在体内对于正常 淋巴细胞生理学和炎症。 为了验证这一假设， 将：1）评估体内血细胞上的α-4尾突变体; 2）使用 一组突变体，以确定负责 迁移、粘附增强、与已知细胞骨架共聚 整合素α-4尾的蛋白质和其他专门功能; 和3）比较磷酸肌醇合成和其它信号传导功能 K562细胞、CHO细胞和原代细胞中野生型和突变型α-4的表达 来源于RAG-2嵌合小鼠的淋巴细胞。 使用minimal 具有最大功能效应的突变将使他能够连接 结论是α-4特异性的正面和负面功能效应 与特定的共定位蛋白质和特定的信号传导通路 他将有一个独特的机会在体内进行决定性的 正常血液成熟过程中α-4尾的评价， 在炎症期间。 小鼠原代淋巴细胞的利用率 表达突变型和野生型α-4将允许扩展分析 α-4特异性信号通路。

DESCRIPTION (Adapted from the Applicant's Abstract): The cytoplasmic domain of the integrin alpha4 subunit differs markedly from other alpha chain cytoplasmic domains with respect to focal adhesion formation, and this may account for increased cell migration but decreased cell spreading, adhesion strengthening, plasma membrane stiffness, and PIP4,5 synthesis. The principal investigator hypothesizes that distinctive structural features within the alpha-4 tail produce its specialized functions in coordination with specific biochemical associations and signaling pathways. Furthermore the principal investigator hypothesizes these unique features of the alpha-4 tail are critical in vivo for normal lymphocyte physiology and inflammation. To test this hypothesis he will: 1) evaluate alpha-4 tail mutants on blood cells in vivo; 2) use a panel of mutants to determine the exact tail residues responsible for migration, adhesion strengthening, coclustering with known cytoskeletal proteins and other specialized functions of the integrin alpha-4 tail; and 3) compare phosphoinositide synthesis and other signaling functions of wild type and mutant alpha-4 in K562 cells, CHO cells, and primary lymphocytes derived from RAG-2 chimeric mice. The use of minimal mutations with maximal functional effect will allow him to link conclusively alpha-4 specific positive and negative functional effects with specific colocalized proteins and specific signaling pathways Also he will have a unique opportunity to carry out definitive in vivo evaluations of the alpha-4 tail during normal blood maturation and during inflammation. The availability of primary mouse lymphocytes expressing mutant and wild type alpha-4 will allow an expanded analysis of alpha-4 specific signaling pathways.