Frailty: Prediction of Onset and Progression
虚弱:发病和进展的预测
基本信息
- 批准号:10253486
- 负责人:
- 金额:$ 75.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingAnimal ModelAnimalsAssessment toolBehavioralBiologicalC57BL/6 MouseCalciumCharacteristicsComplexCoupledDataDegradation PathwayDevelopmentDwarfismExhibitsFemaleFunctional disorderGenderGene ExpressionHealthHumanImpairmentIn VitroInflammationInflammatoryInterventionInvestigationKnowledgeLongevityMaintenanceMemoryMolecularMovementMusMuscleMuscle ProteinsMuscle functionMyosin ATPaseNatural regenerationOrganismPerformancePersonal SatisfactionPhenotypePhysical FunctionPhysical PerformancePhysiologicalPlant RootsPrevalenceProtein BiosynthesisQuality of lifeRewardsRoleSignal PathwaySkeletal MuscleSocietiesStressSystemSystems AnalysisTestingTimeTranslatingUbiquitinWorkadverse outcomecytokinedesigndisabilityexhaustexperimental studyfrailtyimprovedmalemitochondrial dysfunctionmolecular markermortality riskmouse modelmulticatalytic endopeptidase complexneuromuscularpre-clinicalpreventprotein activationprotein degradationprotein profilingreproductive hormoneresiliencesextooltranscriptometranscriptome sequencing
项目摘要
ABSTRACT
A poorly understood characteristic in the progression of frailty is the earliest time point within the lifespan at
which frailty is first observed (i.e., onset of frailty). The significance of recognizing this critical time point lies in its
potential to discover the biological mechanisms associated with the pre-frail status and to initiate timely
interventions to prevent frailty. Recently, our work with the mouse frailty phenotype, reverse-translated from
human frailty assessment tools (Fried’s frailty phenotype), demonstrate that C57Bl/6 mice model frailty that is
observed in humans. Hence, we have a mouse assessment tool that has potential to capture the onset of frailty
and the associated biological signatures such as physical function, and cellular and molecular biomarkers. Low-
grade inflammation is postulated to be an underlying mechanism of frailty; yet, it is unknown if the onset of frailty
is associated with an enhanced inflammatory state. If inflammation is at the root of the genesis of frailty,
modulating inflammation is likely to be most effective at the early stage of health decline, at a time when the
compensatory capacity of the organism is not completely exhausted. Driven by our robust preliminary data, we
will test the overarching hypothesis that systemic inflammation is the primary trigger regulating the
genesis of frailty through activation of protein degradation pathways in skeletal muscle, resulting in
decreased muscle function and performance. Aim 1 will determine the onset of frailty and the mortality risk
in male and female mice in experiments designed to gain a better understanding of how the mouse frailty
phenotype provides for rigorous testing of frailty across the lifespan and whether changes in neuromuscular
behavioral performance identify the earliest time points at which frailty markers manifest, using two preclinical
animal models, the C57Bl/6 and the Ames dwarf mice. At the same time, we will integrate the assessment of
memory and the inflammatory profile that likely contribute to health decline with age. Experiments in Aim 2 will
delineate the extent to which skeletal muscle health contributes to the development of frailty in C57Bl/6 mice.
Our preliminary data suggest that the muscles of frail mice at the age of frailty onset are in a catabolic state, with
increased inflammatory stress, impaired muscle contractility, and altered gene expression (RNA-seq profile). To
extend our initial evidence on the role of muscle at the onset of frailty, we will examine muscle function, muscle
protein degradation, transcriptome and inflammatory profiles in age-matched frail and robust, nonfrail mice. At
the completion of this project we will: 1) have confirmed and extended the mouse frailty phenotype as a reliable
tool to determine frailty onset; 2) know in detail whether systemic inflammation is a trigger for the initiation of
frailty; 3) know in cellular and molecular detail whether skeletal muscle is a primary driver underlying the decline
in physical performance with frailty; and 4) have gained a better understanding of the contribution of reproductive
hormones and the sex-frailty paradox.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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HOLLY M. BROWN-BORG其他文献
HOLLY M. BROWN-BORG的其他文献
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{{ truncateString('HOLLY M. BROWN-BORG', 18)}}的其他基金
Indians Into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
- 批准号:
10056228 - 财政年份:2019
- 资助金额:
$ 75.95万 - 项目类别:
Indians into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
- 批准号:
10372778 - 财政年份:2019
- 资助金额:
$ 75.95万 - 项目类别:
Indians into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
- 批准号:
10544544 - 财政年份:2019
- 资助金额:
$ 75.95万 - 项目类别:
Fourteenth & Fifteenth International Symposia on Neurobiology & Neuroendocrinology of Aging
第十四
- 批准号:
9899821 - 财政年份:2018
- 资助金额:
$ 75.95万 - 项目类别:
12th and 13th International Symposia on Neurobiology and Neuroendocrinology of Ag
第12届和第13届银神经生物学和神经内分泌学国际研讨会
- 批准号:
9058973 - 财政年份:2014
- 资助金额:
$ 75.95万 - 项目类别:
Biology of Aging Sessions at Meetings of The Gerontological Society of America
美国老年学会会议上的衰老生物学会议
- 批准号:
8257377 - 财政年份:2011
- 资助金额:
$ 75.95万 - 项目类别:
Biology of Aging Sessions at Meetings of The Gerontological Society of America
美国老年学会会议上的衰老生物学会议
- 批准号:
8334061 - 财政年份:2011
- 资助金额:
$ 75.95万 - 项目类别:
Role of GH on thiol metabolism, stress resistance and aging
GH 对硫醇代谢、应激抵抗和衰老的作用
- 批准号:
8323370 - 财政年份:2010
- 资助金额:
$ 75.95万 - 项目类别:
Role of GH on thiol metabolism, stress resistance and aging
GH 对硫醇代谢、应激抵抗和衰老的作用
- 批准号:
8149871 - 财政年份:2010
- 资助金额:
$ 75.95万 - 项目类别:
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