Elucidating Cellular Aging and Quality Control Pathways through Meiotic Differentiation

通过减数分裂分化阐明细胞衰老和质量控制途径

• 批准号: 10299523
• 负责人: Elcin Unal
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299523
• 关键词: Address; Affect; Age; Aging; Animal Model; Area; Behavior; Biochemical; Biological Models; Biology of Aging; Caenorhabditis elegans; Candidate Disease Gene; Cell Aging; Cell Cycle Progression; Cells; Cellular Morphology; Cessation of life; Chromosomes; Complement; Critical Pathways; DNA; Defect; Development; Disease; Dissection; Ectopic Expression; Ensure; Eukaryota; Event; Exclusion; Eye; Family; Functional disorder; Gametogenesis; Gene Targeting; Genes; Genetic; Genetic Recombination; Germ Cells; Goals; Growth; Health; Human; Incentives; Link; Longevity; Malignant Neoplasms; Meiosis; Methods; Mitochondria; Modification; Molecular; Morphogenesis; Nerve Degeneration; Nuclear; Nuclear Pore Complex; Nucleolar Proteins; Oogenesis; Organelles; Pathology; Pathway interactions; Physiological; Predisposition; Process; Production; Proteins; Quality Control; Regenerative Medicine; Regulation; Rejuvenation; Risk Factors; Saccharomyces cerevisiae; Saccharomycetales; Somatic Cell; Spermatogenesis; Structure; System; TP53 gene; Therapeutic; Tissues; Vacuole; Yeasts; age effect; aged; egg; experimental study; fitness; functional decline; gain of function; gene product; healthspan; improved; insight; live cell microscopy; membrane biogenesis; novel strategies; programs; segregation; sperm cell; temporal measurement; transcription factor; Address; Affect; Age; Aging; Animal Model; Area; Behavior; Biochemical; Biological Models; Biology of Aging; Caenorhabditis elegans; Candidate Disease Gene; Cell Aging; Cell Cycle Progression; Cells; Cellular Morphology; Cessation of life; Chromosomes; Complement; Critical Pathways; DNA; Defect; Development; Disease; Dissection; Ectopic Expression; Ensure; Eukaryota; Event; Exclusion; Eye; Family; Functional disorder; Gametogenesis; Gene Targeting; Genes; Genetic; Genetic Recombination; Germ Cells; Goals; Growth; Health; Human; Incentives; Link; Longevity; Malignant Neoplasms; Meiosis; Methods; Mitochondria; Modification; Molecular; Morphogenesis; Nerve Degeneration; Nuclear; Nuclear Pore Complex; Nucleolar Proteins; Oogenesis; Organelles; Pathology; Pathway interactions; Physiological; Predisposition; Process; Production; Proteins; Quality Control; Regenerative Medicine; Regulation; Rejuvenation; Risk Factors; Saccharomyces cerevisiae; Saccharomycetales; Somatic Cell; Spermatogenesis; Structure; System; TP53 gene; Therapeutic; Tissues; Vacuole; Yeasts; age effect; aged; egg; experimental study; fitness; functional decline; gain of function; gene product; healthspan; improved; insight; live cell microscopy; membrane biogenesis; novel strategies; programs; segregation; sperm cell; temporal measurement; transcription factor

PROJECT SUMMARY The primary risk factor for prevalent diseases including cancer and neurodegeneration is aging. At the cellular level, aging manifests as an accumulation of conserved physiological defects that eventually cause functional decline, disease, and organismal death. Despite an extensive list of age-associated dysfunctions, we have a limited understanding of how aging becomes a major disease determinant. The traditional method in the field is to induce genetic modifications in a model organism before the aging process manifests itself, and to subsequently determine how these alterations affect lifespan. While these studies have been instrumental in identifying factors that impact longevity and healthspan, they lack the temporal resolution to distinguish the gene products that directly counteract age-associated damage from those that have indirect effects on lifespan, merely through delaying cell cycle progression, growth and/or development. The key challenge is the development of an effective system that allows identification of the underlying mechanisms of aging and manipulation of identified factors in a controlled manner. My lab has discovered that gametogenesis, the differentiation program that gives rise to reproductive cells, contains endogenous rejuvenation pathways. These physiological pathways have the ability to exclude and eliminate both cytoplasmic and nuclear pathologies that are associated with age. Therefore, mechanistic dissection of this program offers unique insights into the biology of aging as well as potential therapeutic avenues for age-associated diseases. This proposal seeks to provide a comprehensive understanding of the molecular and cellular events that are associated with meiotic rejuvenation. The experiments proposed in Aim 1 will determine how gametes are able to exclude and subsequently eliminate nuclear and cytoplasmic defects that accumulate with age. The experiments proposed in Aim 2 will take an orthogonal approach to identify and characterize the complete complement of meiotic genes that are capable of extending lifespan in vegetative yeast cells, akin to metazoan somatic cells. Further extension of these studies to C. elegans will identify conserved meiotic genes that can counteract organellar damage and will determine the effects of activating gametogenesis-specific rejuvenation pathways on tissue-specific as well as organismal healthspan. The combination of studies described in this proposal will reveal a mechanistic understanding of how meiotic rejuvenation occurs at the molecular level, determine which genes improve fitness and lifespan outside of meiosis, and reveal conserved pathways that can be leveraged to extend healthspan.

项目摘要 包括癌症和神经退行性在内的普遍疾病的主要危险因素是衰老。在细胞 水平，衰老表现为保守生理缺陷的积累，最终引起功能 衰落，疾病和有机死亡。尽管大量与年龄相关的功能障碍列表，但我们有一个 对衰老如何成为主要疾病决定因素的有限了解。该领域的传统方法是 在衰老过程之前诱导模型生物中的遗传修饰，并表现出来，并 随后，确定这些改变如何影响寿命。尽管这些研究在 确定影响寿命和健康状况的因素，他们缺乏时间分辨率来区分 基因产物直接抵消对年龄相关的损害的损害，从而对寿命有间接影响， 仅通过延迟细胞周期的进展，生长和/或发育。关键挑战是 开发有效系统，该系统允许识别衰老的潜在机制 以受控方式操纵确定的因素。我的实验室发现了配子发生， 产生生殖细胞的分化程序包含内源性恢复途径。 这些生理途径具有排除和消除细胞质和核的能力 与年龄相关的病理。因此，该程序的机械解剖提供了独特的 洞悉衰老的生物学以及与年龄相关疾病的潜在治疗途径。 该提案旨在对分子和细胞事件进行全面的了解 与减数分裂复兴有关的。 AIM 1中提出的实验将决定配子如何 能够排除并随后消除随着年龄的增长而积累的核和细胞质缺陷。这 AIM 2中提出的实验将采用正交方法来识别和表征完整的 能够在营养酵母细胞中延长寿命的减数分裂基因，类似于后生 体细胞。这些研究进一步扩展到秀丽隐杆线虫将识别可以保守的减数分裂基因 抵消细胞器损害，并将确定激活配子发生特异性复兴的影响 组织特异性和生物健康范围的途径。其中描述的研究组合 提案将揭示对减数分裂复兴如何在分子水平发生的机械理解， 确定哪些基因改善了减数分裂以外的适应性和寿命，并揭示了保守的途径 可以利用以扩展健康范围。