Development of a Mouse Model for Frailty

描述(申请人提供)：这项研究的目标是建立一种虚弱的小鼠模型，该模型可用于未来老年虚弱综合征的病因学和干预研究。在这个模型中寻找的表型特征包括与年龄相关的活动、肌肉力量和体重的下降，以及以炎症细胞因子IL-6水平上升为特征的全身炎症标志物的增加。IL-10TM/tm小鼠对抗NFkB相关炎症激活的能力降低，我们的试点数据表明，IL-10TM/tm小鼠发展出与年龄相关的生理特征，这些特征与虚弱一致。我们假设，与年龄和性别匹配的C57BL/6J对照组小鼠相比，IL-10TM/tm小鼠将随着年龄的增加而发生表型改变，这与人类的虚弱程度一致。我们进一步假设，这些变化将是炎症途径慢性激活的结果。在第一个特定目标中，我们建议通过评估肌肉力量、平衡、体重和活动、全血计数、炎症标志物分布、IGF-1水平和骨骼肌基因表达，纵向和横向比较IL-10TM/tm小鼠和它们的年龄和性别匹配的C57BL/6J对照品系。在具体目标2中，我们建议对共病和死亡的原因进行详细的研究，并在IL-10TM/tm和对照株之间进行比较。在具体目标三中，我们建议扩展我们关于线粒体相关基因表达改变的初步发现，以探索不同年龄段骨骼肌中线粒体的功能。建立由炎症途径慢性激活引起的虚弱小鼠模型，将极大地促进研究人员对虚弱的病因和干预研究的能力，并使人们能够更深入地从生物学上理解虚弱的老年人的现有共病和脆弱性。这个项目的目的是开发一种虚弱的小鼠模型，可以用来更好地理解随着虚弱而发展的生物变化。我们将研究IL-10TM/tm小鼠品系的物理、生理和分子特征，并在几个年龄点将其与对照小鼠品系进行比较。我们希望发现，随着年龄的增长，虚弱的小鼠有更高水平的炎症标志物、肌肉无力和基因表达变化，类似于虚弱的老年人类。

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.