染色体端粒的长度和端粒酶活性与人类的衰老、疾病和肿瘤发生密切相关，端粒体结合蛋白起着调控端粒和端粒酶的作用。在近期用BiFC筛选端粒体结合蛋白的研究工作中，我们发现了TRIM蛋白超家族的成员，TRIM15, 能与TPP1、POT1以及TIN2相互作用。我们推测TRIM15可能作为端粒体蛋白的E3泛素连接酶，影响端粒体蛋白的泛素化和稳定性，从而在端粒调控中起重要作用。申请人拟在本项目支持下，首先利用生化和分子生物学手段在细胞水平揭示TRIM15在端粒调控中的功能和机制，然后运用分子荧光互补技术筛选与TRIM15相互作用的蛋白质，并且制备TRIM15条件基因敲除小鼠模型进行体内功能研究。本研究不仅将推进TRIM15蛋白复合物在端粒调控以及小鼠发育中的作用及分子机制的了解，并且为研究TRIM15在细胞增殖、分化、凋亡、基因转录调控、机体的免疫和发育以及肿瘤发生中的作用提供重要的模式动物。

Telomere length and telomerase activity are closely related to the process of aging，tumorigenesis and pathobiology of some inherited human diseases. Telosome interacting protein are important factors involved in the regulation of telomere and telomerase. In our recent bimolecular fluorescence complementation (BiFC) screening to identify new telosome binding proteins, we found TRIM15, a member of superfamily of the tripartite motif containing (TRIM) proteins, was assocaited with TPP1,POT1 and TIN2. Our hypothesis is that TRIM15 may involve in the ubiquitin-mediated degradation of telomeric proteins as E3 ligase, and is likely to be an novel important factor in telomere regulation. With the support of NSFC, firstly we will use biochemical and molecular biology approach to characterize the function and mechanism of TRIM15 in telomere regulation at the cellular level. Futhermore,we will identify new TRIM15 interacting proteins by BiFC screening. Finally, we will generate TRIM15 conditional knockout mice for in vivo study of TRIM15 function. This study will ont only promote our understanding of the function of TRIM15 complex in telomere regulation and mouse development,but also provide animal model to study the role of TRIM15 in in diverse cell processes including cell proliferation, differentiation, apoptosis, transcriptional regulation, innate immunity and tumorigenesis.