Development of a Mouse Model for Frailty

描述（由申请人提供）：本研究的目的是建立一个虚弱的小鼠模型，该模型可用于未来老年虚弱综合征的病因学和干预研究。在该模型中寻找的表型特征包括与年龄相关的活动、肌肉力量和体重下降，以及以血清炎症细胞因子IL-6水平升高为特征的全身性炎症标志物增加。IL-10tm/tm小鼠对抗NFkB相关炎症激活的能力下降，我们的试点数据显示，IL-10tm/tm小鼠发展出与衰老相关的身体和生理特征，这些特征与虚弱相一致。我们假设，与年龄和性别匹配的C57Bl/6J对照小鼠相比，IL-10tm/tm小鼠会随着年龄的增长而发生与人类虚弱相一致的表型改变。我们进一步假设这些变化是由炎症途径的慢性激活引起的。在第一个具体目标中，我们建议通过评估肌肉力量、平衡、体重和活动、全血细胞计数、炎症标志物谱、IGF-1水平、骨骼肌基因表达，纵向和横切比较IL-10tm/tm小鼠与其年龄和性别匹配的C57Bl/6J对照菌株。在具体的目标2中，我们建议对合并症和死亡率的原因进行详细的研究，并将IL-10tm/tm与对照菌株进行比较。在具体目标三中，我们建议扩展线粒体相关基因表达改变的初步发现，以探索骨骼肌中不同年龄的线粒体功能。由炎症途径的慢性激活引起的虚弱小鼠模型的建立将极大地促进研究人员进行虚弱的病因学和干预研究的能力，并使对虚弱的老年人的现有合并症和脆弱性有更深入的生物学理解。这个项目的目的是建立一个虚弱的小鼠模型，可以用来更好地理解随着虚弱而发展的生物学变化。我们将研究IL-10tm/tm小鼠品系的物理、生理和分子特性，并在几个年龄点与对照小鼠品系进行比较。我们希望发现，随着年龄的增长，体弱多病的老鼠会有更高水平的炎症标志物、肌肉无力和基因表达改变，这与体弱多病的老年人相似。

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.