Regulation of Cellular Behavior in Response to Extracellular Cues

响应细胞外信号的细胞行为调节

• 批准号: 10853789
• 负责人: Clarissa A Henry
• 金额: $ 58.8万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10853789
• 关键词: Acceleration; Affect; Age; Age Years; Aging; Animals; Applications Grants; Area; Atrophic; Award; Behavior; Biological; Biological Process; Biomedical Research; Breeding; Catabolism; Cells; Cellular Membrane; Centers of Research Excellence; Chromosome Mapping; Communities; Cues; Data; Deceleration; Development; Dietary Intervention; Disease; Drama; Elderly; Epigenetic Process; Exercise; FBXO32 gene; Fasting; Female; Fiber; Fishes; Functional disorder; Funding; Future; Genes; Genetic Models; Genotype; Goals; Grant; Health; Health Care Costs; Homeostasis; Human; Image; Individual; Intermittent fasting; Intervention; Island; Killifishes; Knowledge; Laboratories; Laboratory Finding; Light; Link; Locomotion; Longevity; Maine; Maintenance; Medicine; Metabolic; Methods; Modeling; Modification; Molecular; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Natural regeneration; Nutrient; Organism; Outcomes Research; Parents; Pathologic; Pathway interactions; Performance; Persons; Phenotype; Physical Exercise; Physiological; Process; Proteins; Proteomics; Quality of life; Regenerative capacity; Research; Research Project Grants; Role; Running; Signal Pathway; Signal Transduction; Stains; Stimulus; Striated Muscles; Swimming; System; Technical Expertise; Testing; Time; Tissues; Universities; Virus Diseases; Work; World Health Organization; Zebrafish; age related; aged; cell behavior; cell growth regulation; cost; dietary; dietary restriction; environmental intervention; extracellular; gene therapy; genetic manipulation; healthspan; human disease; human model; innovation; male; model organism; mortality risk; multiple omics; muscle aging; muscle degeneration; muscle form; negative affect; novel; organizational structure; overexpression; preservation; programs; protein degradation; proteostasis; reduced muscle mass; regenerative; response; sarcopenia; skeletal muscle wasting; therapeutic candidate; therapeutic development; therapeutic target; tool; transcriptomics; ubiquitin-protein ligase

PROJECT SUMMARY COBRE - 1P20GM144265-01 Parent award goal: The parent award goal is the COBRE Center for the Regulation of Cellular Behavior in Response to Extracellular Cues. This COBRE grant supports 5 junior project leaders from University of Maine (UMaine) and Mount Desert Island Biological Laboratory (MDIBL). The parent award builds organizational structure to run essential research programs and help grow the research community around cohesive common research themes. Research projects funded through the COBRE center for the Regulation of Cellular Behavior in Response to Extracellular Cues will significantly develop our understanding and knowledge regarding the physiological and pathophysiological roles of external stimuli (such as cell-cell communication, signaling pathway, or viral infection) during development, regeneration, health or diseases. Supplement award goal: Title: Proteostasis, atrophy and degeneration in the context of muscle aging Sarcopenia is a multifactorial disease characterized by the loss of muscle mass, strength and function. Associated with aging and age-related diseases, it is a major issue negatively affecting quality of life and the rising cost of health care. The problem with sarcopenia is two-fold: there is a loss of proteostatic maintenance leading to degeneration of muscle fibers as well as a lack of ability to regenerate healthy tissue. During aging, muscle wasting is associated with increased expression of the striated muscle-specific protein turnover factor Atrogin-1. The Madelaine lab found that overexpression of this factor in zebrafish leads to rapid degeneration of muscle fibers, atrophic muscle tissue and locomotor dysfunctions. Surprinsigly, the expression of this factor is also increased under dietary restriction (DR) involving fasting. DR is the most robust aging intervention to increase healthy lifespan and preserve long-term muscle maintenance. As metabolic parameters are reset to match dietary limitations, adaptation to DR temporarily induces muscle catabolism associated with increased atrogin- 1. Interestingly, the Atrogin-1 protein appears to have a central role in proteostasis and muscle homeostatis in the context of both health and disease. Understanding how Atrogin-1 and associated factors regulate muscle proteostasis in different contexts may help in the development of therapeutic approaches to limit muscle atrophy and ameliorate muscle wasting. However, use of vertebrate systems like mice for investigating skeletal muscle wasting in the context of natural aging require several years and comes at great cost. Use of a alternative vertebrate model organisms would allow genetic and environmental interventions at a reduced cost and within a relatively short period of time. The zebrafish is a well established powerful organism for genetic manipulations and modeling of human diseases, while Nothobranchius furzeri (N. furzeri) has recently emerged as a model for investigating both aging and regeneration. N. furzeri is the shortest-lived vertebrate bred in captivity, living only a few months. We propose to use these fish models to investigate muscle maintenance associated with changes in proteostasis and regenerative capacity during aging and/or DR. The Madelaine lab has established a new genetic model of accelerated muscle aging in zebrafish that we will use to leverage modifications associated with increase muscle degeneration and atrophy. The Rogers lab has developed a model of dietary restriction (DR) involving intermittent fasting in N. furzeri that works to increase healthy lifespan in male and female animals. This provides an intervention strategy to mitigate loss of proteostasis and regenerative capacity that occur with age. These different experimental conditions also allows for comparison of the positive role of Atrogin-1 in adaptation to DR with its pathological role in sarcopenia. In order to generate data required to better understand cellular changes associated with muscle aging and to support future grant applications, we want to establish a substantive collaborative effort on the part of our labs. We propose to carry out the following research goals: 1) Test locomotion and swimming performance to determine muscle function in fish models of accelerated muscle aging and after fasting. 2) Assess muscle structural integrity using tissue-clearing and light-sheet imaging in a genetic model of sarcopenia, during aging and under DR. 3) Use a single cell multiomics approach to characterize changes in muscle proteostatic maintenance associated with expression of Atrogin-1, aging and under DR. This supplement award project fits in the scope of the parent award with the objective to identify molecular effectors of muscle aging and cellular changes within the muscle tissue associated with genetic and dietary interventions. The collaborative effort from two labs with complementary technical skills and expertise (accelerated muscle aging and lifespan/healthspan intervention) will strengthen the outcome of this research project.

项目概要 科布雷 - 1P20GM144265-01 家长奖励目标： 家长奖励目标是 COBRE 细胞行为调节中心 对细胞外信号的反应。这笔 COBRE 赠款支持大学的 5 名初级项目负责人 缅因州 (UMaine) 和山漠岛生物实验室 (MDIBL)。家长奖设立 运行重要研究项目并帮助发展研究社区的组织结构 围绕有凝聚力的共同研究主题。由 COBRE 中心资助的研究项目 响应细胞外信号的细胞行为调节将显着发展我们的 关于外部因素的生理和病理生理作用的理解和知识 发育过程中的刺激（例如细胞间通讯、信号传导途径或病毒感染）， 再生、健康或疾病。 补充奖励目标： 标题：肌肉衰老背景下的蛋白质稳态、萎缩和退化 肌肉减少症是一种多因素疾病，其特征是肌肉质量、力量和功能的丧失 功能。与衰老和年龄相关疾病相关，是对质量产生负面影响的主要问题 生活的恶化和医疗费用的上涨。肌肉减少症的问题有两个： 蛋白质静态维持导致肌纤维变性以及缺乏能力 再生健康组织。在衰老过程中，肌肉萎缩与 横纹肌特异性蛋白周转因子 Atrogin-1。马德琳实验室发现过度表达 斑马鱼体内的这一因子会导致肌纤维快速退化、肌肉组织萎缩 运动功能障碍。令人惊讶的是，该因子的表达在饮食条件下也增加了 限制（DR）涉及禁食。 DR 是延长健康寿命的最有力的衰老干预措施 并保持长期的肌肉维持。随着代谢参数被重置以匹配饮食 局限性，对 DR 的适应会暂时诱导与 atrogin 增加相关的肌肉分解代谢。 1. 有趣的是，Atrogin-1 蛋白似乎在蛋白质稳态和肌肉中具有核心作用 健康和疾病背景下的稳态。了解 Atrogin-1 及其关联方式 在不同情况下调节肌肉蛋白质稳态的因素可能有助于治疗药物的开发 限制肌肉萎缩和改善肌肉萎缩的方法。然而，使用脊椎动物系统 就像老鼠一样，研究自然衰老背景下骨骼肌的消耗需要几年的时间 并且代价高昂。使用替代脊椎动物模型生物体将允许遗传和 以较低的成本并在相对较短的时间内进行环境干预。 斑马鱼是一种功能强大的生物体，可用于遗传操作和建模 人类疾病，而 Nothobranchiusfurzeri（N.furzeri）最近已成为人类疾病的模型 研究衰老和再生。 N. Furzeri 是人工饲养的寿命最短的脊椎动物， 只活了几个月。我们建议使用这些鱼类模型来研究肌肉维护 与衰老和/或 DR 期间蛋白质稳态和再生能力的变化有关。这 马德莱恩实验室建立了斑马鱼加速肌肉老化的新遗传模型，我们将 用于利用与增加肌肉退化和萎缩相关的修饰。罗杰斯夫妇 实验室开发了一种饮食限制 (DR) 模型，其中包括对绒毛猪笼草进行间歇性禁食，该模型有效 延长雄性和雌性动物的健康寿命。这提供了一种干预策略来缓解 随着年龄的增长，蛋白质稳态和再生能力丧失。这些不同的实验 条件还允许比较 Atrogin-1 在适应 DR 中的积极作用与其 在肌肉减少症中的病理作用。为了生成更好地了解细胞变化所需的数据 与肌肉老化相关并支持未来的拨款申请，我们希望建立一个实质性的 我们实验室的协作努力。我们建议开展以下研究目标：1）测试 运动和游泳性能以确定加速鱼模型中的肌肉功能 肌肉老化和禁食后。 2) 使用组织清除和光片评估肌肉结构完整性 衰老期间和 DR 下肌肉减少症遗传模型的成像。 3) 使用单细胞多组学 表征与表达相关的肌肉蛋白稳定维持变化的方法 Atrogin-1，老化且处于 DR 状态。 该补充奖励项目符合家长奖励的范围，目的是确定 肌肉衰老的分子效应和与肌肉组织相关的细胞变化 遗传和饮食干预。两个技术互补的实验室的合作努力 技能和专业知识（加速肌肉老化和寿命/健康干预）将加强 该研究项目的成果。