Investigating the role of Alzheimer's disease familial mutations in neuromuscular physiology

研究阿尔茨海默病家族突变在神经肌肉生理学中的作用

基本信息

  • 批准号:
    10448570
  • 负责人:
  • 金额:
    $ 76.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-15 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary There are few in vitro models that examine Alzheimer’s disease (AD) pathology outside the central nervous system. Several studies have indicated the lack of appropriate preclinical Alzheimer’s Disease and Related Dementias (ADRD) models as one of the barriers for successful development of AD/ADRD therapeutics. Motor impairment is a common feature of early AD pathology and the link between motor function and the risk of developing AD has been increasingly recognized. Gait abnormalities have been found to precede the onset of dementia by many years. It is now becoming apparent that treatment windows and thus clinical trials must shift to the mild cognitive impairment (MCI) or better yet the pre-MCI stage to be effective, however, there are few if any diagnostics to predict who will develop AD at this stage of the disease. Studies have demonstrated that motor dysfunction early in AD seems to predict cognitive and functional decline, institutionalization, and mortality. Thus, a preclinical screening model based on a functional assay composed of human cells to evaluate the effects of amyloidopathy and tauopathy in the motor and sensory segments of the peripheral nervous system (PNS) enables a platform for understanding multiplicative effects in AD and potentially identify biomarkers that could identify high risk AD patients at the preclincial stage, thus improving their clinical outcomes. We seek to use UCF’s functional systems to investigate AD in terms of deficits in sensory and motor function in collaboration with Dr. Morgan at MSU to complement our CNS AD functional models in response to the NOSI: Sensory and Motor System Changes as Predictors of Preclinical Alzheimer’s Disease (NOT-AG-20-053). Recently, Hickman published a model of the neuromuscular junction (NMJ) composed of human motoneurons (MNs) and human primary skeletal muscle (SkM) myotubes cultured in a serum-free medium for applications to ALS using iPSC derived mutant MNs. The system, with two chambers linked by microtunnels, supports axonal outgrowth to the muscle chamber and facilitated MN-stimulated SkM contraction as well as direct stimulation-induced SkM contraction. We also have established a functional sensory neuronal system where intrafusal fibers can be innervated by sensory neurons, stretched and the AP generation monitored at the neuronal cell body that can be integrated with piezoelectric sensors and actuators. We propose establishing a PNS model for AD using Aβ42 and tau oligomer dosed healthy systems in addition to motor and sensory systems composed of AD mutant iPSC-derived NMJ systems as an extension of our recently published CNS AD model. We hypothesize our AD PNS systems will exhibit characteristic disease pathology as well as uncover distinct functional deficits useful in a preclinical diagnostic capacity. We will determine functional deficits induced by the oligomers as well as monitor biomarkers in the medium to identify which biomarkers could be used in a companion blood test. We have preliminary data that Aβ oligomers have a deleterious effect on MN and NMJ function. Development of in vitro models of the PNS without cortical neuron components could establish definitively the effects of AD in the PNS.
Project Summary There are few in vitro models that examine Alzheimer’s disease (AD) pathology outside the central nervous system. Several studies have indicated the lack of appropriate preclinical Alzheimer’s Disease and Related Dementias (ADRD) models as one of the barriers for successful development of AD/ADRD therapeutics. Motor impairment is a common feature of early AD pathology and the link between motor function and the risk of developing AD has been increasingly recognized. Gait abnormalities have been found to precede the onset of dementia by many years. It is now becoming apparent that treatment windows and thus clinical trials must shift to the mild cognitive impairment (MCI) or better yet the pre-MCI stage to be effective, however, there are few if any diagnostics to predict who will develop AD at this stage of the disease. Studies have demonstrated that motor dysfunction early in AD seems to predict cognitive and functional decline, institutionalization, and mortality. Thus, a preclinical screening model based on a functional assay composed of human cells to evaluate the effects of amyloidopathy and tauopathy in the motor and sensory segments of the peripheral nervous system (PNS) enables a platform for understanding multiplicative effects in AD and potentially identify biomarkers that could identify high risk AD patients at the preclincial stage, thus improving their clinical outcomes. We seek to use UCF’s functional systems to investigate AD in terms of deficits in sensory and motor function in collaboration with Dr. Morgan at MSU to complement our CNS AD functional models in response to the NOSI: Sensory and Motor System Changes as Predictors of Preclinical Alzheimer’s Disease (NOT-AG-20-053). Recently, Hickman published a model of the neuromuscular junction (NMJ) composed of human motoneurons (MNs) and human primary skeletal muscle (SkM) myotubes cultured in a serum-free medium for applications to ALS using iPSC derived mutant MNs. The system, with two chambers linked by microtunnels, supports axonal outgrowth to the muscle chamber and facilitated MN-stimulated SkM contraction as well as direct stimulation-induced SkM contraction. We also have established a functional sensory neuronal system where intrafusal fibers can be innervated by sensory neurons, stretched and the AP generation monitored at the neuronal cell body that can be integrated with piezoelectric sensors and actuators. We propose establishing a PNS model for AD using Aβ42 and tau oligomer dosed healthy systems in addition to motor and sensory systems composed of AD mutant iPSC-derived NMJ systems as an extension of our recently published CNS AD model. We hypothesize our AD PNS systems will exhibit characteristic disease pathology as well as uncover distinct functional deficits useful in a preclinical diagnostic capacity. We will determine functional deficits induced by the oligomers as well as monitor biomarkers in the medium to identify which biomarkers could be used in a companion blood test. We have preliminary data that Aβ oligomers have a deleterious effect on MN and NMJ function. Development of in vitro models of the PNS without cortical neuron components could establish definitively the effects of AD in the PNS.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

James J Hickman其他文献

James J Hickman的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('James J Hickman', 18)}}的其他基金

Investigating the role of Alzheimer's disease familial mutations in neuromuscular physiology
研究阿尔茨海默病家族突变在神经肌肉生理学中的作用
  • 批准号:
    10620712
  • 财政年份:
    2022
  • 资助金额:
    $ 76.46万
  • 项目类别:
Modulatory Role of Blood-Brain-Barrier and Enzymatic Activity in an Innovative Human Model of Cholinergic Drug Induced Dementia
血脑屏障和酶活性在胆碱能药物诱发痴呆的创新人类模型中的调节作用
  • 批准号:
    10258975
  • 财政年份:
    2021
  • 资助金额:
    $ 76.46万
  • 项目类别:
Hesperos Diversity Supplement forgrant number 1 R44AG071386
Hesperos 多样性补充补助金编号 1 R44AG071386
  • 批准号:
    10577655
  • 财政年份:
    2021
  • 资助金额:
    $ 76.46万
  • 项目类别:
Populating MPS database with data from multi-organ, human-on-a-chip microphysiological systems
用来自多器官、人体芯片微生理系统的数据填充 MPS 数据库
  • 批准号:
    10435269
  • 财政年份:
    2021
  • 资助金额:
    $ 76.46万
  • 项目类别:
Modulatory Role of Blood-Brain-Barrier and Enzymatic Activity in an Innovative Human Model of Cholinergic Drug Induced Dementia
血脑屏障和酶活性在胆碱能药物诱发痴呆的创新人类模型中的调节作用
  • 批准号:
    10467040
  • 财政年份:
    2021
  • 资助金额:
    $ 76.46万
  • 项目类别:
Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity
多器官人体芯片系统解决用药过量、急慢性疗效和脱靶毒性问题
  • 批准号:
    10351973
  • 财政年份:
    2019
  • 资助金额:
    $ 76.46万
  • 项目类别:
Drug-drug interactions for antivirals with opioids and Narcan in a 5- organ human-on-a-chip model
抗病毒药物与阿片类药物和纳洛酮在 5 器官芯片模型中的药物相互作用
  • 批准号:
    10224388
  • 财政年份:
    2019
  • 资助金额:
    $ 76.46万
  • 项目类别:
Human on a chip systems to investigate disease comorbidities common in the aged population
人类芯片系统研究老年人群中常见的疾病合并症
  • 批准号:
    10402384
  • 财政年份:
    2018
  • 资助金额:
    $ 76.46万
  • 项目类别:
Human on a chip system to investigate genetic risk factors in Alzheimer's disease
人类芯片系统研究阿尔茨海默病的遗传风险因素
  • 批准号:
    9628532
  • 财政年份:
    2018
  • 资助金额:
    $ 76.46万
  • 项目类别:
Development of an integrated 4-organ animal model
综合四器官动物模型的开发
  • 批准号:
    9986123
  • 财政年份:
    2018
  • 资助金额:
    $ 76.46万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
    n/a
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
  • 批准号:
    2341426
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
  • 批准号:
    2341424
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Continuing Grant
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政​​策的情绪动态
  • 批准号:
    10108433
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
  • 批准号:
    MR/X032809/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
  • 批准号:
    MR/X034690/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Fellowship
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
  • 批准号:
    24K13490
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
  • 批准号:
    EP/Z00022X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
  • 批准号:
    MR/Y003365/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
  • 批准号:
    2335955
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
  • 批准号:
    AH/Y007549/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.46万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了