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: 10657538
• 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/10657538
• 关键词: Affect; Age; Aging; Area; Behavior; Biochemical; Biological Models; Biology of Aging; Caenorhabditis elegans; Candidate Disease Gene; Cell Aging; Cell Cycle Progression; Cell model; Cells; Cellular Morphology; Cessation of life; Chromosomes; Complement; Critical Pathways; Cytoplasm; DNA; Dedications; Defect; Deterioration; Development; Disease; Dissection; Ectopic Expression; Ensure; Eukaryota; Event; Exclusion; Eye; Family; Functional disorder; Gametogenesis; Gene Targeting; Genes; Genetic; Genetic Induction; Genetic Recombination; Germ Cells; Goals; Growth; Health; Homologous Gene; 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; System; TP53 gene; Therapeutic; Tissues; Vacuole; Yeasts; age effect; aged; cell injury; egg; experimental study; fitness; functional decline; gain of function; gene product; healthspan; improved; insight; live cell microscopy; membrane biogenesis; model organism; novel strategies; precursor cell; programs; public health relevance; 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.

项目概要 癌症和神经退行性疾病等流行疾病的主要危险因素是衰老。在蜂窝 在一定程度上，衰老表现为保守的生理缺陷的积累，最终导致功能障碍 衰退、疾病和有机体死亡。尽管存在大量与年龄相关的功能障碍，但我们有一个 对衰老如何成为主要疾病决定因素的了解有限。现场传统的方法是 在衰老过程显现之前诱导模型生物体进行基因修饰，并 随后确定这些改变如何影响寿命。虽然这些研究有助于 在识别影响寿命和健康寿命的因素时，他们缺乏时间分辨率来区分 直接抵消与年龄相关的损害的基因产物，这些损害来自对寿命有间接影响的基因产物， 仅通过延迟细胞周期进程、生长和/或发育。关键的挑战是 开发一个有效的系统，可以识别衰老和衰老的根本机制 以受控方式操纵已识别的因素。我的实验室发现配子发生 产生生殖细胞的分化程序包含内源性复兴途径。 这些生理途径具有排除和消除细胞质和细胞核的能力。 与年龄相关的病理。因此，对该程序的机械剖析提供了独特的 对衰老生物学以及与年龄相关疾病的潜在治疗途径的见解。 该提案旨在提供对分子和细胞事件的全面理解 与减数分裂复兴有关。目标 1 中提出的实验将确定配子如何 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 目标 2 中提出的实验将采用正交方法来识别和表征完整的 减数分裂基因的补充，能够延长营养酵母细胞的寿命，类似于后生动物 体细胞。将这些研究进一步扩展到秀丽隐杆线虫，将鉴定出保守的减数分裂基因，这些基因可以 抵消细胞器损伤，并将确定激活配子发生特异性复兴的效果 组织特异性以及有机体健康寿命的途径。本文描述的研究组合 该提案将揭示减数分裂复兴如何在分子水平上发生的机制理解， 确定哪些基因可以改善减数分裂之外的适应性和寿命，并揭示保守的途径 可以用来延长健康寿命。

项目成果

Effects of Pea (Pisum sativum L.) Cultivars for Mixed Cropping with Oats (Avena sativa L.) on Yield and Competition Indices in an Organic Production System.

• DOI: 10.3390/plants11212936
• 发表时间: 2022-10-31
• 期刊: Plants (Basel, Switzerland)
• 作者: Šarūnaitė L;Toleikienė M;Arlauskienė A;Razbadauskienė K;Deveikytė I;Supronienė S;Semaškienė R;Kadžiulienė Ž
• 通讯作者: Kadžiulienė Ž

5G Standalone and 4G Multi-Carrier Network-in-a-Box Using a Software Defined Radio Framework.

• DOI: 10.3390/s21165653
• 发表时间: 2021-08-22
• 期刊: Sensors (Basel, Switzerland)
• 作者: Kiela K;Jurgo M;Macaitis V;Navickas R
• 通讯作者: Navickas R

Meiotic nuclear pore complex remodeling provides key insights into nuclear basket organization.

减数分裂核孔复合物的重塑为核篮组织提供了关键的见解。

• DOI: 10.1083/jcb.202204039
• 发表时间: 2023-02-06
• 期刊: The Journal of cell biology

Assessing hemodynamics from the photoplethysmogram to gain insights into vascular age: a review from VascAgeNet.

• DOI: 10.1152/ajpheart.00392.2021
• 发表时间: 2022-04-01
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Charlton PH;Paliakaitė B;Pilt K;Bachler M;Zanelli S;Kulin D;Allen J;Hallab M;Bianchini E;Mayer CC;Terentes-Printzios D;Dittrich V;Hametner B;Veerasingam D;Žikić D;Marozas V
• 通讯作者: Marozas V

Concrete Modular Pavement Structures with Optimized Thickness Based on Characteristics of High Performance Concrete Mixtures with Fibers and Silica Fume.

具有优化厚度的混凝土模块化路面结构，基于高性能混凝土混合物与纤维和二氧化硅烟雾的特征。

• DOI: 10.3390/ma14123423
• 发表时间: 2021-06-21
• 期刊: Materials (Basel, Switzerland)
• 作者: Vaitkus A;Gražulytė J;Šernas O;Karbočius M;Mickevič R
• 通讯作者: Mickevič R