Genetic Analysis of Germ Cell Immortality

 描述（由申请人提供）：生殖细胞保持自身处于原始状态，允许其从一代传递到下一代时无限增殖。相比之下，体细胞，包括体干细胞，只需要一个单一的世代，并可能缺乏确保无限增殖能力的机制。生殖细胞和索马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，如肿瘤发生。该项目的长期目标是研究生殖细胞保持无限增殖能力的机制。我们发现C. elegans Piwi同源物prg-1通过小RNA介导的表观基因组沉默促进生殖细胞永生，并且Piwi/皮尔纳突变体的跨代生育缺陷可以通过激活主要的体细胞长寿途径来抑制。我们建议1）研究胰岛素/IGF-1信号通路如何抑制Piwi突变体的跨代生育缺陷，2）研究Piwi突变体的不育表型，这可能代表一种假死状态，3）更彻底地探索Piwi突变体的跨代不育表型如何被抑制。拟议的实验应该提供洞察1）一种可遗传的表观遗传应激形式，可以通过生殖细胞传播，2）生物体对高水平这种应激的反应。我们可以揭示与衰老的代际调节相关的基本原理。

 DESCRIPTION (provided by applicant): Germ cells maintain themselves in a pristine condition that allows for indefinite proliferation as they are passed from one generation to the next. In contrast, somatic cells, including somatic stem cells, are only needed for a single generation and may 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. We discovered that the C. elegans Piwi homolog prg-1 promotes germ cell immortality via small RNA-mediated silencing of the epigenome and that the transgenerational fertility defect of Piwi/piRNA mutants can be suppressed by activation of a major somatic longevity pathway. We propose 1) to study how the insulin/IGF-1 signaling pathway suppresses the transgenerational fertility defect of Piwi mutants, 2) to study the sterilit phenotype of Piwi mutants, which may represent a state of suspended animation, and 3) to more thoroughly explore how the transgenerational sterility phenotype of Piwi mutants can be suppressed. The proposed experiments should provide insight into 1) a form of heritable epigenetic stress that can be transmitted by germ cells and 2) the organismal response to high levels of this stress. We could uncover fundamental principles relevant to transgenerational regulation of aging.