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.

项目概要 细胞器参与稳态过程以改善细胞健康。然而，一些细胞器蛋白 体细胞可以存活数月，因此在衰老过程中很容易受到损害。在种系中，配子 在将细胞器内容物传递给下一代之前，它们可能会被长期逮捕。 因此，使易受损伤的蛋白质在种系中持久存在会出现问题，并对能力提出挑战。 生殖细胞将健康物质代代相传。卵母细胞成熟后 受精时，某些母体产物被降解，以启动发育中的母体向合子的转变 胚胎，尽管很少有人知道母体来源的细胞器是如何被翻转并被合子取代的 细胞器。有趣的是，质量控制事件已被证明发生在单细胞生物体中，并且在 不对称分裂以确保消除细胞器长寿命蛋白（LLP）。然而，无论 进行专门的细胞器质量控制，以去除发育后代中母体衍生的 LLP，以及 这一过程如何在多细胞生物体中发生仍然知之甚少。通过分子 和遗传分析，该奖学金提出的研究将调查母体细胞器输入如何 来自果蝇卵母细胞的卵母细胞影响其后代的种系健康。首先我会内生标记好 表征了 LLP，以可视化合子蛋白质池以及母体衍生的长寿命蛋白质池 胚胎、幼虫和成年后代的蛋白质相同。通过对母体和合子进行差异标记 池中，我将比较后代种系中的蛋白质水平，以评估它是否选择性地阻止母体沉积 细胞器 LLP 可以跨代遗传。接下来，我将扰乱卵母细胞的健康，以研究孕产妇如何 受损的 LLP 有助于后代的生存能力。最后，我将确定其他长寿蛋白质 使用双正交氨基酸标记方法从母体细胞器中提取并比较它们的命运 具有良好特征的 LLP 的后代种系。拟议的实验将强调母性如何 衍生的 LLP 影响后代种系中的细胞器功能。此外，这些研究将揭示 阐明细胞器在世代之间如何保持连续性，旨在揭示专门的质量控制 种系中的途径。