Aging and the nuclear lamina in mitotic stem cells

有丝分裂干细胞的衰老和核层

• 批准号: 10209608
• 负责人: PAMELA K. GEYER
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10209608
• 关键词: ATR gene; Address; Affect; Age; Aging; Biological Aging; Biosensor; CHEK2 gene; Cell Count; Cell Differentiation process; Cell Maintenance; Cell division; Cells; Centrosome; Cessation of life; Data; Daughter; Deterioration; Development; Disease; Dissection; Drosophila genus; Exhibits; Failure; Female; Female infertility; Frequencies; Functional disorder; Future; Generations; Goals; Homeostasis; Human; Impairment; Lamins; Mitosis; Mitotic; Mitotic spindle; Molecular; Monitor; Morphology; Nuclear; Nuclear Envelope; Nuclear Lamina; Phosphotransferases; Physiological; Premature aging syndrome; Process; Production; Progeria; Proteins; Role; Structure; Testing; Therapeutic; Tissues; adult stem cell; age effect; age related; defined contribution; experimental study; falls; germline stem cells; in vivo; injured; insight; invention; mutant; novel; self-renewal; stem cell aging; stem cell division; stem cell function; stem cell homeostasis; stem cell population; stem cell proliferation; stem cells; tool

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.

项目概要 组织稳态取决于分化细胞的调节产生以取代 那些损坏或有缺陷的。体内平衡随着年龄的增长而下降，主要原因是 干细胞数量和/或功能减少。要干预衰老过程，关键是 了解干细胞稳态的机制。我们发现范式 果蝇雌性生殖干细胞（fGSC）使用非典型的有丝分裂模式，其中 在整个有丝分裂过程中，核膜和核纤层仍然存在。在这种模式下，有丝分裂 纺锤体从嵌入保留核层的中心体成核。这种模式 由于干细胞分裂的稀有性和全球范围内的有丝分裂的发生未被认识到 公认的假设是后生动物有丝分裂涉及核层扩散。因此，如何 有丝分裂核层影响不对称干细胞分裂和干细胞维持 未知。这些研究的长期目标是确定有丝分裂核的贡献 衰老过程中层板与 fGSC 的稳态。我们利用这种天然的体内干细胞 表现出干细胞功能快速、年龄依赖性下降的人群，以解决 两个目标。目标 1 将定义生物衰老如何影响有丝分裂核层。目标2将 定义核纤层检查点激酶在生理衰老中的作用。实验于 该提案将确定新发现的有丝分裂核层对阻止 细胞维护。这些研究有可能深入了解核纤层蛋白相关的 疾病，如早衰症，并为推进延迟或延迟治疗提供见解 消除自然衰老过程中干细胞的损失。