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

基本信息

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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
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)
影响因子：
0
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.

DOI：
10.1083/jcb.202204039
发表时间：
2023-02-06
期刊：
The Journal of cell biology
影响因子：
0
作者：
通讯作者：

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
影响因子：
0
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.