Genetic Analysis of Germ Cell Immortality

描述（由申请人提供）：生殖细胞被设计为保持有效的无限增殖能力，以实现其生物学目的：无限期地从一代传递到下一代。相比之下，体细胞，包括体细胞干细胞，只需要一代。因此，体细胞可能缺乏确保无限增殖能力的机制。生殖细胞和体细胞之间的这种二分法可能是人类增殖性衰老的最终原因，并可能导致一些与年龄有关的疾病，如肿瘤发生。该项目的长期目标是研究生殖细胞维持无限增殖能力的机制。许多秀丽隐杆线虫致命的生殖系突变体损害生殖细胞不朽已被分离。有限数量的致命生殖系突变体将被绘制遗传图谱并被克隆。这些致命的生殖系突变体的表型将被表征，并促进生殖细胞不朽的机制将被研究。途径分析将通过构建双突变体来进行，这将揭示不同形式的增殖性损伤如何在体内相互作用。本文将研究秀丽隐杆线虫致死性种系突变体的增殖与有丝分裂后衰老的关系。本项目利用正向遗传学研究生殖细胞在全动物体内增殖不朽的分子基础。这个项目将定义一些基因和几种途径，除了端粒酶，抑制生殖细胞的增殖老化。其中一些基因或途径可能在哺乳动物体细胞中缺乏，因此可能影响我们的衰老方式。

DESCRIPTION (provided by applicant): Germ cells are designed to maintain an effectively unlimited proliferative capacity in order to fulfill their biological purpose: to be passed from one generation to the next, indefinitely. In contrast, somatic cells, including somatic stem cells, are only needed for a single generation. Somatic cells may therefore be deficient for mechanisms that ensure an unlimited proliferative capacity. This dichotomy between germ and soma cells may be the ultimate cause of human proliferative aging and may contribute to some age-related diseases such as tumorigenesis. The long-term goal of this project is to study the mechanisms by which germ cells maintain an unlimited proliferative capacity. Many C. elegans mortal germline mutants that are compromised for germ cell immortality have been isolated. A limited number of mortal germline mutants will be mapped genetically and cloned. The phenotypes of these mortal germline mutants will be characterized, and mechanisms that promote germ cell immortality will be investigated. Pathway analysis will be conducted by constructing double mutants, which ought to reveal how different forms of proliferative damage interact in vivo. The relationship between proliferative and post-mitotic aging will be studied for some C. elegans mortal germline mutants. This project utilizes forward genetics to study the molecular basis of the proliferative immortality of germ cells in whole animals. This project will define a number of genes and several pathways, aside from telomerase, that repress proliferative aging in germ cells. Some of these genes or pathways may be deficient in mammalian somatic cells and may therefore affect how we age.