Genetic Analysis of Germ Cell Immortality

描述(申请人提供)：生殖细胞被设计为保持有效的无限增殖能力，以实现它们的生物学目的：无限期地从一代传到下一代。相比之下，体细胞，包括体细胞干细胞，只需要一代人。因此，体细胞可能缺乏确保无限增殖能力的机制。生殖细胞和胞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相关的疾病，如肿瘤形成。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。许多线虫致命的生殖系突变体已经被分离出来，这些突变体的生殖细胞永生能力受到了影响。将对数量有限的人类生殖系突变进行遗传作图和克隆。这些致命的生殖系突变体的表型将被描述，促进生殖细胞永生的机制将被研究。途径分析将通过构建双突变来进行，这应该会揭示不同形式的增殖性损伤在体内是如何相互作用的。将对一些线虫致命种系突变体的增殖衰老和有丝分裂后衰老之间的关系进行研究。本项目利用正向遗传学研究整个动物生殖细胞增殖永生的分子基础。该项目将定义除端粒酶以外的一些基因和几条抑制生殖细胞增殖性衰老的途径。其中一些基因或途径可能在哺乳动物体细胞中缺乏，因此可能会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.