Macrophages to Enhance Recovery of Skeletal Muscle following Disuse Atrophy in Aging

巨噬细胞可增强衰老废用性萎缩后骨骼肌的恢复

基本信息

批准号：
9395538
负责人：
Paul Timothy Reidy
金额：
$ 5.67万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9395538
关键词：
Adult Aging Anti-Inflammatory Agents Anti-inflammatory Automobile Driving Biology Cell Differentiation process Cell Proliferation Cells Characteristics Chemotactic Factors Chemotaxis Clinical Data Disuse Atrophy Educational workshop Elderly Event Exposure to Fellowship Flow Cytometry Genetic Goals Grant Human Immune Immune response Immunology Immunotherapy Impairment Inflammatory Injection of therapeutic agent Injury K-Series Research Career Programs Knockout Mice Ligands Macrophage Colony-Stimulating Factor Mentors Metabolism Methodology Methods Modeling Molecular Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Myeloid Cells Patients Pattern Phenotype Positioning Attribute Process Productivity Recovery Recovery of Function Recruitment Activity Reperfusion Injury Research Personnel Research Project Grants Risk Rodent Role Skeletal Muscle Technology Testing Time Training Treatment Efficacy Universities Utah age related aging population angiogenesis career chemokine disability effective therapy experience experimental study fall risk fibrogenesis follow-up immunoregulation improved injured innovation insight mRNA Expression macrophage monocyte mouse model muscle aging muscle regeneration novel novel strategies novel therapeutic intervention novel therapeutics physical inactivity prevent response satellite cell skeletal muscle wasting skill acquisition tool

Adult Aging Anti-Inflammatory Agents Anti-inflammatory Automobile Driving Biology Cell Differentiation process Cell Proliferation Cells Characteristics Chemotactic Factors Chemotaxis Clinical Data Disuse Atrophy Educational workshop Elderly Event Exposure to Fellowship Flow Cytometry Genetic Goals Grant Human Immune Immune response Immunology Immunotherapy Impairment Inflammatory Injection of therapeutic agent Injury K-Series Research Career Programs Knockout Mice Ligands Macrophage Colony-Stimulating Factor Mentors Metabolism Methodology Methods Modeling Molecular Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Myeloid Cells Patients Pattern Phenotype Positioning Attribute Process Productivity Recovery Recovery of Function Recruitment Activity Reperfusion Injury Research Personnel Research Project Grants Risk Rodent Role Skeletal Muscle Technology Testing Time Training Treatment Efficacy Universities Utah age related aging population angiogenesis career chemokine disability effective therapy experience experimental study fall risk fibrogenesis follow-up immunoregulation improved injured innovation insight mRNA Expression macrophage monocyte mouse model muscle aging muscle regeneration novel novel strategies novel therapeutic intervention novel therapeutics physical inactivity prevent response satellite cell skeletal muscle wasting skill acquisition tool

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项目摘要

Project Summary/Abstract Older adults are at risk to be injured, ill, and hospitalized resulting in physical inactivity-induced muscle atrophy and weakness. Moreover, older adults have an impaired muscle recovery following disuse. Therefore, there exists a need to further understand the cellular mechanisms behind this impaired muscle regrowth with aging. Macrophages are of vital importance during the muscle regrowth following disuse atrophy, however, their role under such conditions in aging skeletal muscle has surprisingly not been previously elucidated. Therefore, using a mouse model of disuse atrophy and regrowth of skeletal muscle, Dr. Reidy and mentoring team have compiled convincing preliminary data demonstrating an impaired muscle regrowth in aging mice and this is accompanied by a blunted macrophage immune response (recruitment and activation of muscle macrophages) in skeletal muscle during muscle recovery. Therefore, I have proposed to conduct an extensive time course of the muscle macrophage response in old and young mice during recovery from disuse (Aim 1) in order to reveal key time points for novel therapeutic intervention. Macrophage immunotherapy and immunomodulation has been successful to improve muscle recovery following ischemia-reperfusion injury and recovery from disuse in young mice. Given the impaired regrowth in aging skeletal muscle and the potential impact of macrophage therapy the goal of Aim 2 is to use macrophage immunotherapy and immunomodulation to restore the regrowth in aging skeletal muscle following disuse. My preliminary data suggested that aging skeletal muscle has impaired macrophage recruitment, and further supported by a decrease in the mRNA expression, of a pivotal chemotactic factor, chemokine (C-C motif) ligand 2 (CCL2). As a follow-up to Aim 2, we will determine if inhibiting macrophage recruitment (CCL2 KO mice) will result in a phenotype characteristic of old mice during recovery from disuse. We plan to use this data to develop a career development award for follow-up mechanistic and parallel human experiments. Additionally, the research project during this fellowship will be tied with various training experiences including new skill acquisition and exposure to aging and metabolism seminars, grant workshops, and interdisciplinary interactions.

项目摘要/摘要老年人有受伤，病和住院的风险，导致身体不活跃肌肉萎缩和无力。此外，老年人的肌肉恢复受损废弃后。因此，有必要进一步了解细胞机制随着衰老而受损的肌肉再生。巨噬细胞至关重要然而，废除萎缩后的肌肉再生，它们在这种情况下在衰老中的作用骨骼肌以前尚未阐明。因此，使用鼠标 Reidy博士和指导团队的骨骼肌萎缩和再生模型编译令人信服的初步数据，证明了衰老小鼠的肌肉再生受损这伴随着巨大的巨噬细胞免疫反应（招募和肌肉恢复过程中骨骼肌的肌肉巨噬细胞的激活。因此，我提议在旧的肌肉巨噬细胞反应中进行广泛的时间过程和年轻的老鼠从废弃（AIM 1）中恢复（AIM 1），以揭示新颖的关键时间点治疗干预。巨噬细胞免疫疗法和免疫调节已经在缺血 - 再灌注损伤和从在年轻老鼠中废弃。鉴于老化骨骼肌的再生和潜力受损巨噬细胞疗法的影响目标2是使用巨噬细胞免疫疗法和免疫调节以恢复废弃后老化骨骼肌的再生。我的初步数据表明，衰老的骨骼肌损害了巨噬细胞的募集，并进一步支持mRNA表达的降低，关键趋化因子的mRNA表达，趋化因子（C-C基序）配体2（CCL2）。作为AIM 2的后续行动，我们将确定是否抑制巨噬细胞募集（CCL2 KO小鼠）将导致旧小鼠的表型在恢复废弃期间。我们计划使用这些数据开发职业发展奖用于后续机械和平行的人类实验。此外，研究项目在此奖学金期间，将与包括新技能获取在内的各种培训经验并列以及接触衰老和代谢研讨会，授予研讨会和跨学科互动。