Cellular rejuvenation during oogenesis

卵子发生过程中的细胞再生

• 批准号: 10864188
• 负责人: Maya Capelson
• 金额: $ 38.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10864188
• 关键词: Abnormal Cell; Address; Age; Aging; Alzheimer' s Disease; Animals; Automobile Driving; Autophagocytosis; Biological; Biological Assay; Cells; Data; Defect; Development; Developmental Biology; Disease; Drosophila genus; Ensure; Epigenetic Process; Excision; Exhibits; Female; Fertility; Functional disorder; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Genome; Germ Cells; Goals; Heterochromatin; Image; Link; Longevity; Maintenance; Mediating; Membrane Proteins; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Nuclear Accidents; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Oocytes; Oogenesis; Parents; Pathway interactions; Phenotype; Physiological; Protein Biosynthesis; Proteins; Quality Control; RNA Interference; Recycling; Regenerative Medicine; Rejuvenation; Research; Role; Specific qualifier value; Starvation; Structure; Testing; Tissue imaging; Up-Regulation; Yeasts; acute stress; cell injury; design; fitness; germline stem cells; next generation; oocyte maturation; overexpression; programs; promoter; protein complex; protein degradation; regenerative therapy; spatiotemporal; sperm cell; stem cell differentiation; tissue fixing; tool

Dysfunction of the nuclear pore complex (NPC) has been extensively linked to aging and neurodegenerative conditions such as ALS and Alzheimer’s disease. NPCs are large nuclear envelope-embedded protein complexes composed of about 30 Nucleoporin (Nups) that regulate nucleocytoplasmic exchange as well as genome function. Many Nups exhibit unusually slow turnover and thus accumulate damage with age, which is thought to contribute to age-associated NPC dysfunction and loss of cellular fitness. Recent studies revealed that defective NPCs and acute stress induce NPC recycling via autophagy in yeast, but whether this mechanism occurs in metazoans and its physiological relevance are unknown. Damaged cellular machinery can lead to organismal dysfunction and aging, yet irrespective of the age of the parents, the gametes, such as oocyte and sperm, ensure that the next generation starts afresh with undamaged components. Our labs investigate the mechanisms underlying the differentiation of germline stem cells (GSCs) into oocytes, the only cells of the female that contribute to the next generation and defy aging, and physiological roles of the NPC. Autophagy appears to be active during GSC differentiation in Drosophila, but the biological significance is not completely understood. We recently described pathways required for a germ cell-to-maternal transition during Drosophila oogenesis that is required for oocyte specification and maintenance. We demonstrated that early oogenesis genes are silenced during this transition via a mechanism involving heterochromatin and NPCs, and that heterochromatin formation during mid-oogenesis triggers upregulation of most Nups. Our preliminary results suggest that NPCs undergo extensive removal during this critical window of oogenesis, which overlaps with transcriptional induction of Nups. Additionally, we found that an autophagy factor Atg8 can be targeted to NPCs during germ cell-to-maternal transition and that loss of Atg8 leads to germ cell abnormalities and aberrant expression of early oogenesis genes. Thus, our central hypothesis is that selective autophagy and programmed transcription underlie an “NPC rejuvenation” program during oocyte specification to ensure oocyte viability and progeny fitness. We plan to address this hypothesis with the following three specific aims: 1) Define the spatiotemporal dynamics of NPC turnover during the germ cell-to-maternal transition; 2) Determine the factors that promote NPC rejuvenation during the germ cell-to-maternal transition; and 3) Determine the biological relevance of NPC rejuvenation pathways to oogenesis and fertility. We expect to discover that the germ cell-to-maternal transition resets cellular lifespan in part by driving a developmentally regulated NPC rejuvenation program, involving coordinated clearance of old NPCs by autophagy and the synthesis of new NPCs via heterochromatin formation-dependent transcription. We anticipate our research will uncover new concepts in developmental biology, regenerative medicine, and aging.

核孔复合物（NPC）的功能障碍已与衰老和神经退行性相关 ALS和阿尔茨海默氏病等疾病。 NPC是大型核包膜包裹的蛋白 由大约30个核孔蛋白（NUP）组成的复合物，这些核孔（NUP）调节核细胞质交换以及 基因组功能。许多NUP暴露了很少缓慢的营业额，因此随着年龄的增长而丙烯酸的损害，即 被认为有助于与年龄相关的NPC功能障碍和细胞适应性丧失。最近的研究表明 NPC和急性应力有缺陷诱导NPC通过酵母中的自噬进行回收，但是这种机制是否存在 发生在后生动物中，其身体相关性是未知的。受损的蜂窝机械可能导致 有机功能障碍和老化，但无论父母的年龄，卵母细胞和诸如gamestes的年龄如何 精子，确保下一代以未受损的组件重新开始。我们的实验室调查了 种系干细胞（GSC）分化为卵母细胞的机制，雌性唯一的细胞 这有助于下一代和反抗衰老，以及NPC的身体角色。自噬似乎是 在果蝇中的GSC分化过程中保持活跃，但尚未完全了解生物学。 我们最近描述了在果蝇期间生殖细胞到母体过渡所需的途径 卵母细胞规范和维护需要。我们证明了早期的卵子基因被沉默 在这种过渡期间，通过涉及异染色质和NPC的机制，以及异染色质形成 在中期期间，大多数NUP会触发上调。我们的初步结果表明NPC经历了 在这个关键的卵子发生窗口中，广泛的去除与NUP的转录诱导重叠。 此外，我们发现在生殖细胞到母细胞期间可以将自噬因子ATG8靶向NPC 过渡和ATG8的丧失导致生殖细胞异常和早期卵子发生的异常表达 基因。那就是我们的中心假设是选择性自噬和编程的转录是 卵母细胞规范期间的“ NPC恢复活力”计划，以确保卵母细胞的生存能力和进度健身。我们计划 通过以下三个特定目的解决这一假设：1）定义NPC的时空动力学 生殖细胞到母体过渡期间的营业额； 2）确定促进NPC修订的因素 在生殖细胞到母体过渡期间； 3）确定NPC修订的生物学相关性 卵子发生和生育的途径。我们希望发现生殖细胞到母体过渡重置细胞 寿命部分是通过开发受过开发的NPC修订计划，涉及协调的 自噬清除旧的NPC，并通过异染色质形成依赖于新的NPC 转录。我们预计我们的研究将发现发育生物学的新概念，再生 医学和衰老。