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.

核孔复合体 (NPC) 的功能障碍与衰老和神经退行性疾病广泛相关 ALS 和阿尔茨海默氏病等疾病中的 NPC 是大型核膜包埋蛋白。 由约 30 个核孔蛋白 (Nups) 组成的复合物，调节核细胞质交换以及 许多Nups表现出异常缓慢的更新，因此随着年龄的增长而积累损伤，这是 最近的研究表明，这被认为会导致与年龄相关的鼻咽癌功能障碍和细胞健康丧失。 有缺陷的 NPC 和急性应激通过酵母中的自噬诱导 NPC 回收，但这种机制是否 发生在后生动物中，其生理相关性尚不清楚。受损的细胞机制可能导致。 机体功能障碍和衰老，但无论父母的年龄如何，配子，例如卵母细胞和 精子，确保下一代以未受损的成分重新开始。 生殖系干细胞 (GSC) 分化为卵母细胞（女性唯一的细胞）的机制 有助于下一代并抵抗衰老，而自噬似乎与 NPC 的生理作用有关。 在果蝇的 GSC 分化过程中具有活性，但其生物学意义尚不完全清楚。 我们最近描述了果蝇卵子发生过程中生殖细胞向母体转变所需的途径 我们证明了早期卵子发生基因是沉默的。 在此转变过程中，通过涉及异染色质和 NPC 的机制，以及异染色质的形成 我们的初步结果表明，在卵子发生中期，NPC 会发生上调。 在卵子发生的这个关键窗口期间被广泛去除，这与 Nups 的转录诱导重叠。 此外，我们发现自噬因子 Atg8 可以在生殖细胞到母体的过程中靶向 NPC。 Atg8 的缺失会导致生殖细胞异常和早期卵子发生的异常表达 因此，我们的中心假设是选择性自噬和程序化转录是基因的基础。 我们计划在卵母细胞规格过程中实施“NPC 年轻化”计划，以确保卵母细胞的活力和后代的健康状况。 为了解决这个假设，有以下三个具体目标：1）定义 NPC 的时空动态 2）确定促进NPC返老还童的因素； 生殖细胞向母体转变期间；3) 确定 NPC 返老还童的生物学相关性 我们期望发现生殖细胞到母体的转变会重置细胞。 延长寿命的部分方法是推动一项受发育调节的 NPC 复兴计划，其中包括协调一致 通过自噬清除旧的 NPC，并通过异染色质形成依赖性合成新的 NPC 我们预计我们的研究将揭示发育生物学、再生学的新概念。 医学、衰老。