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.

项目摘要 COBRE -1P20GM144265-01 父母奖励目标： 父级奖励目标是对细胞行为调节的毛线中心 对细胞外提示的反应。该毛线赠款支持大学的5名初级项目负责人 缅因州（Umaine）和荒岛山生物实验室（MDIBL）家长奖建立 组织结构以运行基本的研究计划并帮助发展研究界 围绕着凝聚力的共同研究主题。通过山羊中心资助的研究项目 响应细胞外提示的细胞行为调节将显着发展我们的 了解外部生理和病理生理作用的知识和知识 发育过程中的刺激（例如细胞 - 细胞通信，信号通路或病毒感染）， 再生，健康或疾病。 补充奖励目标： 标题：肌肉衰老的背景下的蛋白质症，萎缩和变性 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。与衰老和与年龄有关的疾病相关，这是一个负面影响质量的主要问题 生活和医疗保健成本的上升。肌肉减少症的问题是两个方面：损失 蛋白抑制性维护导致肌肉纤维退化，并且缺乏能力 再生健康组织。在衰老期间，肌肉浪费与增加的表达有关 条纹肌肉特异性蛋白质周转因子Atrogin-1。 Madelaine实验室发现过表达 斑马鱼中的这一因素导致肌肉纤维，萎缩肌肉组织和 运动功能障碍。令人惊讶的是，在饮食中，该因素的表达也会增加 涉及禁食的限制（DR）。 DR是增加健康寿命的最强大的衰老干预措施 并保留长期的肌肉维护。由于代谢参数已重置以匹配饮食 局限性，适应DR会暂时诱导与阿特罗蛋白增加有关的肌肉分解代谢 1。有趣的是，Atrogin-1蛋白在蛋白质和肌肉中似乎具有核心作用 在健康和疾病的背景下，体内平衡。了解Atrogin-1和关联 在不同情况下调节肌肉蛋白质的因素可能有助于治疗的发展 限制肌肉萎缩和改善肌肉浪费的方法。但是，使用脊椎动物系统 像在自然衰老的背景下调查骨骼肌浪费的小鼠一样需要几年 并付出了代价。使用替代脊椎动物模型生物将允许遗传和 环境干预以降低的成本和相对较短的时间内。 斑马鱼是一种良好的强大生物体，用于遗传操作和建模 人类疾病，而Nothobranchius Furzeri（N。Furzeri）最近出现了 研究衰老和再生。 N. furzeri是最短的脊椎动物，被囚禁， 只生活几个月。我们建议使用这些鱼类模型调查肌肉维护 与衰老和/或DR期间的蛋白质量和再生能力的变化有关。这 Madelaine Lab已建立了一种在斑马鱼中加速肌肉衰老的新遗传模型，我们将 用于利用与增加肌肉变性和萎缩有关的修改。罗杰斯 实验室已经开发了一种饮食限制模型（DR），涉及在N. furzeri中进行间歇性禁食的模型 增加男性和雌性动物的健康寿命。这提供了减轻干预策略 随着年龄的增长而发生的蛋白质量和再生能力的丧失。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 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 与肌肉衰老相关并支持未来的赠款应用，我们希望建立一个实质性的 我们实验室的协作努力。我们建议实现以下研究目标：1）测试 运动和游泳表现，以确定加速的鱼类模型中的肌肉功能 肌肉衰老和禁食后。 2）使用组织清除和灯显示评估肌肉结构完整性 在肌肉减少症的遗传模型中成像，在衰老和DR下进行成像。 3）使用单个单元格 表征与表达相关的肌肉蛋白抑制维持变化的方法 Atrogin-1，衰老和DR。 该补充奖项项目符合父母奖的范围，目的是确定 与 遗传和饮食干预措施。两个实验室的合作努力与互补的技术 技能和专业知识（加速的肌肉衰老和寿命/健康范围的干预）将加强 该研究项目的结果。