Aging and the nuclear lamina in mitotic stem cells

项目总结 组织动态平衡依赖于分化细胞的调节生产来替代 那些损坏或有缺陷的。动态平衡随着年龄的增长而下降，这主要是因为 干细胞数量和/或功能减少。为了干预衰老过程，至关重要的是 了解干细胞动态平衡的机制。我们发现，范型 果蝇雌性生殖系干细胞(FGSC)使用非规范的有丝分裂模式，其中 核膜和核层在整个有丝分裂过程中都保持不变。在这种模式下，有丝分裂 纺锤体是由嵌入在保留的核层中的中心体形成的。此模式 由于干细胞分裂的罕见和全球范围内的 后生动物有丝分裂涉及核板扩散的公认假设。因此，如何 有丝分裂核层影响干细胞不对称分裂和干细胞维持 未知。这些研究的长期目标是确定有丝分裂核的贡献。 在衰老过程中叶片到fGSC的动态平衡。我们利用这种天然的体内干细胞 表现出干细胞功能快速、随年龄下降的人群 两个目标。目标1将定义生物老化如何影响有丝分裂核层。目标2将 明确核层检查点蛋白在生理性衰老中的作用。实验在 这项提案将确立新发现的有丝分裂核层对干细胞的贡献 牢房维护。这些研究有可能提供对层粘连蛋白相关的洞察。 疾病，如早衰症和提供洞察力的先进的治疗方法，延迟或 消除自然老化过程中的干细胞丢失。

PROJECT SUMMARY Tissue homeostasis depends upon the regulated production of differentiated cells to replace those that are damaged or defective. Homeostasis declines with age, largely because of decreases in stem cell number and/or function. To intervene in the aging process, it is critical to understand mechanisms involved in stem cell homeostasis. We discovered that paradigmatic Drosophila female germline stem cells (fGSCs) use a non-canonical mode of mitosis, wherein the nuclear envelope and nuclear lamina remain throughout mitosis. In this mode, mitotic spindles are nucleated from centrosomes embedded in the retained nuclear lamina. This mode of mitosis has gone unrecognized, due to the rarity of stem cell divisions and the globally accepted assumption that metazoan mitoses involve nuclear lamina dispersal. As such, how the mitotic nuclear lamina impacts asymmetric stem cell divisions and stem cell maintenance is unknown. The long-term goal of these studies is to define contributions of the mitotic nuclear lamina to fGSC homeostasis during aging. We capitalize on this natural in vivo stem cell population that demonstrates rapid, age-dependent declines in stem cell functions to address two aims. Aim 1 will define how biological aging affects the mitotic nuclear lamina. Aim 2 will define the role of the nuclear lamina checkpoint kinases in physiological aging. Experiments in this proposal will establish contributions of the newly identified mitotic nuclear lamina to stem cell maintenance. These studies have the potential to provide insights into lamin associated diseases such as progeria and provide insights to advance therapeutics that delay or eliminate stem cell loss during natural aging.