Maternal organelle contribution to offspring germline health

母体细胞器对后代种系健康的贡献

• 批准号: 10607418
• 负责人: Jay S Goodman
• 金额: $ 6.68万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607418
• 关键词: Adult; Age; Aging; Amino Acids; Automobile Driving; Biochemical; Biological; Biological Assay; Cell Nucleus; Cells; Cellular Structures; Chemicals; Complex; Deposition; Deterioration; Development; Diet; Drosophila genus; Drosophila melanogaster; Electron Transport; Embryo; Embryonic Development; Ensure; Event; Exhibits; Fellowship; Female; Fertilization; Generations; Genetic; Germ Cells; Health; Inherited; Label; Larva; Membrane; Methionine-tRNA Ligase; Methods; Mitochondria; Molecular; Molecular Analysis; Nuclear Envelope; Nuclear Pore Complex; Oocytes; Organelles; Organism; Oxidative Phosphorylation; Partner in relationship; Pathway interactions; Phosphorylation; Physiologic pulse; Play; Predisposition; Process; Proteins; Quality Control; Rejuvenation; Repression; Research; Role; Scaffolding Protein; Tissues; Transcript; Visualization; aged; env Gene Products; experimental study; genetic analysis; improved; interdisciplinary approach; male; model organism; mutant; nanobodies; neuronal cell body; next generation; novel; offspring; oocyte maturation; overexpression; premature; prevent; protein complex; protein degradation; transmission process; young adult

Project Summary Organelles engage in homeostatic processes to improve cellular health. However, some organelle proteins in the soma can survive many months, making them susceptible to damage during aging. In the germline, gametes can be arrested for a prolonged period before they pass down their organelle content to the next generation. Having damage-prone proteins perdure in the germline would therefore be problematic and challenge the ability of germ cells to pass down healthy material from generation to generation. Upon oocyte maturation and fertilization, certain maternal products are degraded to initiate the maternal to zygotic transition in the developing embryo, though little is known how maternally derived organelles are turned over and replaced with zygotic organelles. Intriguingly, quality control events have been shown to take place in single cell organisms and during asymmetric divisions to ensure the elimination of organelle long-lived proteins (LLPs). However, whether specialized organelle quality control takes places to remove maternally derived LLPs in developing progeny, and how such a process would take place in a multi-cellular organism remains poorly understood. Through molecular and genetic analysis, the research proposed in this fellowship will investigate how maternal organelle input derived from Drosophila oocytes influences germline health of their offspring. First, I will endogenously tag well characterized LLPs to visualize the zygotic pool of proteins along with the maternally derived long-lived pool of the same protein across embryonic, larval and adult progeny. By differentially tagging the maternal and zygotic pool, I will compare protein levels in the progeny germline to assess if it selectively prevents maternally deposited organelle LLPs to be transgenerationally inherited. Next, I will perturb oocyte health to investigate how maternally damaged LLPs contributes to offspring viability. Finally, I will identify additional long-lived proteins that are derived from maternal organelles using a biorthogonal amino acid labeling approach and compare their fates in the progeny germline with well characterized LLPs. The proposed experiments will highlight how maternally derived LLPs impact organelle function in the germline of ensuing progeny. In addition, these studies will shed light on how organelle continuity is maintained between generations and aim to reveal specialized quality control pathways in the germline.

项目摘要 细胞器进行稳态过程以改善细胞健康。但是，一些细胞器蛋白 Soma可以生存数月，使它们在衰老过程中易受损害。在种系中，配子 在将细胞器内容传递给下一代之前，可以长时间逮捕。 因此，在种系中具有容易损害的蛋白质会是有问题的，并挑战能力 生殖细胞的产生量产生的健康材料。卵母细胞成熟和 受精，某些产妇产品被降解以在发育中启动孕产妇为二卵形过渡 胚胎，虽然鲜为人知的是如何将母体衍生的细胞器翻转并用滞型替换 细胞器。有趣的是，质量控制事件已显示在单细胞生物和期间发生 不对称分裂，以确保消除细胞器长寿命蛋白（LLP）。但是，是否 专门的Organelle质量控制正在删除在发展后代的母体衍生的LLP，并且 在多细胞生物体中，这种过程将如何发生仍然很熟悉。通过分子 和遗传分析，该研究金提出的研究将研究母体细胞器的输入 源自果蝇卵母细胞会影响其后代的种系健康。首先，我会很好地标记 表征了LLP，以可视化蛋白质的合子库以及母体得出的长寿命库 跨胚胎，幼虫和成人后代的相同蛋白质。通过差异标记母体和合子 池，我将比较后代种系中的蛋白质水平，以评估它是否有选择地防止母体沉积 细胞器llps是跨代遗传的。接下来，我将扰动卵母细胞健康，以调查母亲 受损的LLP有助于后代生存能力。最后，我将确定其他长寿命蛋白 使用生物联管氨基酸标记方法源自母体细胞器，并比较其命运 具有良好特征LLP的后代种系。提出的实验将突出显示母亲的方式 衍生的LLP会影响随后的后代种系中的细胞器功能。此外，这些研究将丢弃 阐明了几代人之间如何保持细胞器的连续性，并旨在揭示专业质量控制 种系中的途径。