Muscle weakness and neurogeneration; exercise as a therapeutic approach

肌肉无力和神经发生；

基本信息

批准号：
10287587
负责人：
Karyn A Esser
金额：
$ 37.43万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287587
关键词：
Administrative Supplement Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Animal Model Appearance Area Attenuated Award Biological Assay Body Composition Body Weights and Measures Brain Brain region Clinical Research Clinical Trials Cognitive deficits Collection Complement Data Dementia Disease Exercise Female Fiber Frontotemporal Dementia Grant Health Hippocampus (Brain)Histologic Human Hypothalamic structure Injections Learning Link Maps Measures Memory Mitochondria Modeling Molecular Motor Multiomic Data Mus Muscle Muscle Fibers Muscle Weakness Muscular Atrophy Nerve Degeneration Neurodegenerative Disorders Outcome Parents Pathology Pathway interactions Patients Phenotype Physical activity Positioning Attribute Protocols documentation Regulation Reporting Research Research Personnel Resources Running Serum Skeletal Muscle Study models Tauopathies Therapeutic Therapeutic Intervention Time Tissues Training Transducers United States National Institutes of Health VO2max base brain health brain tissue cerebral atrophy cognitive performance endurance exercise exercise intervention exercise training experimental study functional outcomes interdisciplinary approach male metabolomics molecular site mouse model multiple omics muscle form muscle strength mutant power analysis preclinical study response sarcopenia sex skeletal muscle metabolism tau Proteins transcriptome sequencing transcriptomics treadmill treadmill training

项目摘要

Abstract: This administrative supplement is submitted in response to Notice Number: NOT-AG-20-034: Alzheimer's Disease Administrative supplements for NIH grants. This supplement outlines experiments to extend the parent U01 (UF PASS: Regulation of exercise transducers) to pursue the interaction between exercise, skeletal muscle health and progression of pathology in a mouse model of Alzheimer’s disease (AD). The parent award is part of the MoTrPAC consortium that combines well defined exercise interventions with multi-omics analysis to develop a map of molecular transducers that link exercise to systemic health. For this administrative supplement we will use a defined mouse model of AD with a treadmill training protocol based on the protocol used for MoTrPAC. We will also be in a position to analyze our outcomes data in the context of the larger multiomics data available from MoTrPAC to expand our understanding of potential cross tissue interpretations. A major challenge in the field of Alzheimer’s disease (AD) is the poor understanding of how tau pathology promotes disease. Consequently, therapeutic interventions are ineffective and clinical trials for AD have failed. The working model for this supplement is that exercise mitigates the onset and progression of AD tau pathology through impacting skeletal muscle health as well as direct effects on the brain. The rationale for this model comes from two complementary but not fully explored sub-fields: “AD and muscle/sarcopenia” and “AD and exercise”. Several clinical studies have reported that muscle weakness and loss of muscle mass occurs at a faster rate in AD patients. These muscle changes in the patients are also associated with brain atrophy and diminished cognitive performance. In addition, several studies using animal models of AD have demonstrated changes in skeletal muscle metabolism at times prior to the appearance of AD pathology in the brain. These observations are consistent with our preliminary data that found significant muscle weakness in a tauopathy mouse model of AD prior to overt signs of neurodegeneration. There are also a large number of clinical and preclinical studies showing that exercise training, primarily endurance exercise, has a positive impact on the onset and progression of AD. Thus, we propose to integrate the concepts of exercise, muscle health and brain health to define molecules and pathways that attenuate the onset and progression of AD tau pathology in the brain. We propose the following Specific Aims. Aim 1) To determine the molecular, histological and phenotypic changes in skeletal muscle and brain in an acquired tauopathy model of AD in mice. Aim 2) To use a running exercise intervention with the AD-tauopathy mouse model to identify molecular sites through which tau pathology is attenuated.

摘要：本行政补充是为了响应通知号而提交的：NOT-AG-20-034： NIH 拨款的阿尔茨海默病行政补充本补充概述了以下实验。扩展父U01（UF PASS：运动传感器的调节）以追求之间的相互作用阿尔茨海默病 (AD) 小鼠模型中的运动、骨骼肌健康和病理进展。家长奖是 MoTrPAC 联盟的一部分，该联盟将明确的运动干预措施与为此，通过多组学分析来开发将运动与全身健康联系起来的分子传感器图谱。行政补充我们将使用一个定义的AD小鼠模型和基于跑步机训练协议我们还将能够在 MoTrPAC 的背景下分析我们的结果数据。 MoTrPAC 提供更大的多组学数据，以扩展我们对潜在跨组织的理解解释。阿尔茨海默氏病 (AD) 领域的一个主要挑战是对 tau 蛋白病理学了解甚少经测试，治疗干预无效，AD 临床试验失败。该补充剂的工作模型是运动可以减轻 AD tau 的发生和进展通过影响骨骼肌健康以及对大脑的直接影响来研究病理学。该模型来自两个互补但尚未充分探索的子领域：“AD 和肌肉/肌肉减少症”和“AD 一些临床研究表明，肌肉无力和肌肉质量损失发生在 AD 患者的这些肌肉变化也与脑萎缩有关。此外，一些使用AD动物模型的研究已经证明认知能力下降。在大脑中出现 AD 病理之前，骨骼肌代谢有时会发生变化。观察结果与我们发现 tau 蛋白病患者明显肌肉无力的初步数据一致 AD小鼠模型之前也存在大量的临床和神经变性迹象。临床前研究表明，运动训练，主要是耐力运动，对因此，我们建议整合运动、肌肉健康和大脑的概念。健康来定义减轻 AD tau 病理学的发生和进展的分子和途径我们提出以下具体目标。目的 1) 确定骨骼肌和大脑的分子、组织学和表型变化在小鼠获得性 AD tau 病模型中。目标 2) 使用跑步运动干预 AD-tau 蛋白病小鼠模型来识别 tau 病理学减弱的分子位点。