Development of a Mouse Model for Frailty

衰弱小鼠模型的开发

• 批准号: 7314547
• 负责人: Jeremy D Walston
• 金额: $ 20.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314547
• 关键词: Age; Apoptosis; Biological; Biological Markers; Biology; Characteristics; Chronic; Chronic Disease; Complete Blood Count; Condition; Cross-Sectional Studies; Data; Depth; Development; Elderly; Ensure; Equilibrium; Exposure to; Frail Elderly; Future; Gender; Gene Expression; Genes; Goals; Health; Heterogeneity; Human; Human Characteristics; Infection; Inflammation; Inflammatory; Insulin-Like Growth Factor I; Interleukin-6; Intervention Studies; Knowledge; Longitudinal Studies; Measures; Mediator of activation protein; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Muscle Weakness; Outcome; Oxygen Consumption; Pathway interactions; Phenotype; Physiological; Pilot Projects; Population; Prevalence; Purpose; Rate; Research Design; Research Personnel; Risk; Screening procedure; Serum; Skeletal Muscle; Syndrome; System; Testing; Therapeutic Intervention; Time; Validation; Weight; Weight Gain; age related; base; cytokine; experience; frailty; glucose metabolism; mortality; mouse model; multidisciplinary; muscle strength

DESCRIPTION (provided by applicant): The goal of this study is to establish a frail mouse model that can be utilized in future etiologic and intervention studies of the geriatric syndrome of frailty. The phenotypic characteristics sought in this model include age related declines in activity, muscle strength, and weight, and increased markers systemic inflammation as characterized by increased serum levels of the inflammatory cytokine IL-6. The IL-10tm/tm mouse has a decreased ability to counter NFkB related inflammatory activation, and our pilot data that shows that the IL-10tm/tm mouse develops age-related physical and physiological features that are consistent with frailty. We hypothesize that the IL-10tm/tm mouse will develop phenotypic alterations with increasing age consistent with human frailty as compared to age and gender matched C57Bl/6J control mice. We further hypothesize that these changes will result from the chronic activation of inflammatory pathways. In the first specific aim, we propose to longitudinally and cross-sectionally compare IL-10tm/tm mice with their age and gender matched C57Bl/6J control strain through assessments of muscle strength, balance, weight, and activity, complete blood counts, inflammatory marker profile, IGF-1 levels, skeletal muscle gene expression. In specific aim 2, we propose to develop detailed studies of the causes of co-morbidities and mortality and compare them between IL-10tm/tm and control strain. In specific aim three, we propose to extend our preliminary findings of altered mitochondrial related gene expression to explore mitochondrial function at different ages in skeletal muscle. The establishment of a frail mouse model caused by chronic activation of inflammatory pathways will greatly facilitate the ability of investigators to perform both etiologic and intervention studies of frailty, and enable a deeper biological understanding of incumbent co-morbidities and vulnerabilities of frail, older adults. The purpose of this project is to develop a frail mouse model that can be utilized to better understand the biological changes that develop with frailty. We will study the physical, physiological and molecular characteristics of the IL-10tm/tm mouse strain and compare it to a control mouse strain at several age points. We expect to find that the frail mouse has higher levels of inflammatory markers, muscle weakness, and altered gene expression as it gets older, similar to what is found in frail, older humans.

描述（由申请人提供）：这项研究的目的是建立一个脆弱的小鼠模型，该模型可用于脆弱的老年综合症的未来病因和干预研究。该模型中寻求的表型特征包括与年龄相关的活动，肌肉强度和体重的下降，并增加了标记的全身性炎症，其特征是炎性细胞因子IL-6的血清水平升高。 IL-10TM/TM小鼠具有反应与NFKB相关炎症激活的能力降低，我们的试验数据表明，IL-10TM/TM小鼠会发展与年龄相关的物理和生理特征，这些特征与脆弱一致。我们假设与年龄和性别匹配的C57BL/6J对照小鼠相比，IL-10TM/TM小鼠将随着年龄的增长与人类脆弱的年龄一致而发展表型改变。我们进一步假设这些变化将是由于炎症途径的慢性激活而导致的。在第一个特定目的中，我们建议通过评估肌肉力量，平衡，体重和活动，炎症标记，IGF-1水平，IGF-1水平，IGF-1水平，骨骼肌肉基因的表达，通过评估肌肉力量，平衡，体重和活动，将IL-10TM/TM小鼠与年龄和性别相匹配的IL-10TM/TM小鼠进行比较。在特定的目标2中，我们建议对合并症和死亡率的原因进行详细研究，并将其在IL-10TM/TM和控制菌株之间进行比较。在特定目标三中，我们建议扩展我们对线粒体相关基因表达改变的初步发现，以探索骨骼肌不同年龄的线粒体功能。由炎症途径的长期激活引起的脆弱小鼠模型的建立将极大地促进研究人员对脆弱的病因学和干预研究的能力，并使对现有的合并症和脆弱的脆弱性有更深入的生物学理解。该项目的目的是开发一种脆弱的鼠标模型，该模型可以用来更好地了解脆弱的生物学变化。我们将研究IL-10TM/TM小鼠应变的物理，生理和分子特征，并将其与几个年龄点的对照小鼠菌株进行比较。我们希望发现脆弱的小鼠具有更高水平的炎症标记，肌肉无力和随着年龄的增长而改变的基因表达，类似于脆弱的老年人。