Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain

识别关键运动组织中的弹性蛋白,这些蛋白会导致运动和认知能力下降,并抵消大脑内外 ADRD 病理的负面影响

基本信息

  • 批准号:
    10369971
  • 负责人:
  • 金额:
    $ 135.45万
  • 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:
    2022-04-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Movement is a volitional behavior linked to Alzheimer’s disease and related dementias (ADRD). Though many older adults show some degree of Alzheimer’s disease and related pathologies, the extent that these pathologies degrade movement varies. The same amount of Alzheimer’s disease and related pathologies may be related to rapid decline in one adult and little loss in another. An adult who maintains movement or has a slower rate of decline in the presence of Alzheimer’s disease and related pathologies manifests motor resilience. To promote motor resilience, it is crucial to identify risk factors or proteins that offset the negative effects of Alzheimer’s disease and related pathologies. Shared neural substrate underlies motor and cognitive resources that control movement. So, it’s not surprising that cognitive resilience proteins are related to motor resilience. This study will complement our ongoing discovery of resilience using deep omics in “cognitive” brain regions with deep omics in key “motor regions” to identify new genes and proteins that may provide motor and cognitive resilience. This study responds to NOT-AG-20-053. We selected 3 key motor tissues in which to identify motor resilience proteins that may offset the negative effects of pathologies of Alzheimer’s disease and related dementias (ADRD) and degeneration in motor systems. We will then test if some of these proteins also provide cognitive resilience. Compelling data support this study: 1) Alzheimer’s disease pathology in brainstem and spinal cord is related to a higher odds of dementia. 2) Large individual differences in degeneration of spinal motoneurons, nerve and muscle, highlight the need to measure their degeneration to isolate motor resilience. 3) Our systems biology and protein validation approach applied to RNAseq in dorsal lateral prefrontal cortex (DLPFC) identified cognitive resilience genes and proteins in prior work. 4) This approach can succeed in motor tissues as high quality RNAseq data, summarized as co-expression modules, was obtained from 3 key motor tissues (brain [SMA], spinal cord and muscle) from the same decedents. 5) As hypothesized, after isolating motor resilience, we identified proteins in DLPFC that provide resilience for motor or cognitive decline and some that provide resilience for both. Motor resilience manifests as slower motor decline. We will quantify Alzheimer’s disease and related pathologies in brain, brainstem, spinal cord, nerve and muscle to isolate motor resilience i.e., motor decline not explained by Alzheimer’s disease and related pathologies and degeneration. Aim 1 will apply a systems biology approach to transcriptome data from 3 key motor tissues (brain, spinal cord and muscle) to discover genes that may provide motor resilience. Aim 2 will verify these genes with SRM proteins and validate that these proteins are related to motor decline in an independent sample of adults. Aim 3 will test if motor resilience proteins also provide cognitive resilience and if aggregating multiple proteins into a person-specific index quantifies high and low resilience related to Alzheimer’s disease phenotypes. Aim 4 will test if resilience proteins link risk factors with motor and cognitive decline. Resilience proteins are high value targets for drug discovery to maintain motor and cognitive function despite the presence of untreatable Alzheimer’s disease and related pathologies. These data will also inform on mechanisms underlying motor and cognitive decline and risk factors which provide resilience.
运动是一种与阿尔茨海默病和相关痴呆(ADRD)有关的意志行为。虽然许多老年人表现出一定程度的阿尔茨海默病和相关的病理,这些病理降低运动的程度各不相同。同样数量的阿尔茨海默病和相关病理可能与一个成年人的快速下降和另一个成年人的轻微损失有关。一个成年人谁保持运动或有一个较慢的速度下降,在阿尔茨海默氏病和相关的病理表现出运动弹性。为了促进运动恢复力,确定抵消阿尔茨海默病和相关病理的负面影响的风险因素或蛋白质至关重要。共同的神经基质是控制运动的运动和认知资源的基础。因此,认知弹性蛋白与运动弹性有关也就不足为奇了。这项研究将补充我们正在进行的韧性发现,使用深度组学在“认知”大脑区域与深度组学在关键的“运动区域”,以确定可能提供运动和认知韧性的新基因和蛋白质。 本研究响应NOT-AG-20-053。我们选择了3个关键的运动组织,以确定运动弹性蛋白,这些蛋白可能抵消阿尔茨海默病和相关痴呆症(ADRD)的病理学和运动系统退化的负面影响。然后,我们将测试其中一些蛋白质是否也提供认知弹性。 令人信服的数据支持这项研究:1)脑干和脊髓中的阿尔茨海默病病理学与痴呆症的更高几率有关。2)脊髓运动神经元、神经和肌肉退行性变的巨大个体差异凸显了测量其退行性变以分离运动恢复力的必要性。3)我们的系统生物学和蛋白质验证方法应用于背外侧前额叶皮层(DLPFC)的RNAseq,在先前的工作中鉴定了认知弹性基因和蛋白质。4)这种方法可以在运动组织中取得成功,因为从来自相同死者的3个关键运动组织(脑[SMA]、脊髓和肌肉)获得了高质量的RNAseq数据(总结为共表达模块)。5)正如假设的那样,在分离运动恢复力后,我们确定了DLPFC中为运动或认知下降提供恢复力的蛋白质,以及一些为两者提供恢复力的蛋白质。 运动恢复力表现为较慢的运动衰退。我们将量化阿尔茨海默病和脑、脑干、脊髓、神经和肌肉中的相关病理,以分离运动恢复力,即,不能用阿尔茨海默病和相关病理学和变性解释的运动衰退。目标1将应用系统生物学方法从3个关键运动组织(大脑,脊髓和肌肉)的转录组数据中发现可能提供运动恢复力的基因。目的2将验证这些基因与SRM蛋白,并验证这些蛋白质与运动功能下降在一个独立的成年人样本。目标3将测试运动弹性蛋白是否也提供认知弹性,以及将多种蛋白聚集成一个人特异性指数是否量化与阿尔茨海默病表型相关的高弹性和低弹性。目标4将测试弹性蛋白是否将危险因素与运动和认知能力下降联系起来。弹性蛋白是药物发现的高价值目标,以维持运动和认知功能,尽管存在不可治疗的阿尔茨海默病和相关病理。这些数据还将为运动和认知能力下降的潜在机制以及提供弹性的风险因素提供信息。

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 }}

ARON S BUCHMAN其他文献

ARON S BUCHMAN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('ARON S BUCHMAN', 18)}}的其他基金

Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain
识别关键运动组织中的弹性蛋白,这些蛋白会导致运动和认知能力下降,并抵消大脑内外 ADRD 病理的负面影响
  • 批准号:
    10599328
  • 财政年份:
    2022
  • 资助金额:
    $ 135.45万
  • 项目类别:
Thinking about walking: Can digital phenotyping of mobility improve the prediction of Alzheimer's dementia and inform on the pathologies and proteins contributing to this association?
思考步行:移动的数字表型可以改善阿尔茨海默氏痴呆症的预测并提供有关导致这种关联的病理学和蛋白质的信息吗?
  • 批准号:
    10524888
  • 财政年份:
    2022
  • 资助金额:
    $ 135.45万
  • 项目类别:
Thinking about walking: Can digital phenotyping of mobility improve the prediction of Alzheimer's dementia and inform on the pathologies and proteins contributing to this association?
思考步行:移动的数字表型可以改善阿尔茨海默氏痴呆症的预测并提供有关导致这种关联的病理学和蛋白质的信息吗?
  • 批准号:
    10710174
  • 财政年份:
    2022
  • 资助金额:
    $ 135.45万
  • 项目类别:
Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults
将睡眠呼吸暂停确定为老年人脑干 ADRD 病理的非认知表型
  • 批准号:
    10378737
  • 财政年份:
    2021
  • 资助金额:
    $ 135.45万
  • 项目类别:
Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults
将睡眠呼吸暂停确定为老年人脑干 ADRD 病理的非认知表型
  • 批准号:
    10602556
  • 财政年份:
    2021
  • 资助金额:
    $ 135.45万
  • 项目类别:
Establishing Sleep Apnea as a non-cognitive phenotype of brainstem ADRD pathologies in older adults
将睡眠呼吸暂停确定为老年人脑干 ADRD 病理的非认知表型
  • 批准号:
    10178701
  • 财政年份:
    2021
  • 资助金额:
    $ 135.45万
  • 项目类别:
Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders
阐明阿尔茨海默病及相关疾病中枢神经系统内外活动能力受损的分子驱动因素
  • 批准号:
    10613427
  • 财政年份:
    2019
  • 资助金额:
    $ 135.45万
  • 项目类别:
Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders
阐明阿尔茨海默病及相关疾病中枢神经系统内外活动能力受损的分子驱动因素
  • 批准号:
    9920077
  • 财政年份:
    2019
  • 资助金额:
    $ 135.45万
  • 项目类别:
Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders
阐明阿尔茨海默病及相关疾病中枢神经系统内外活动能力受损的分子驱动因素
  • 批准号:
    10374874
  • 财政年份:
    2019
  • 资助金额:
    $ 135.45万
  • 项目类别:
Impaired Gait in Older Adults: Pathologies of Alzheimer's disease and Related Disorders
老年人步态受损:阿尔茨海默病及相关疾病的病理学
  • 批准号:
    9889016
  • 财政年份:
    2017
  • 资助金额:
    $ 135.45万
  • 项目类别:

相似海外基金

Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
  • 批准号:
    24K18114
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
  • 批准号:
    498288
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
  • 批准号:
    10089306
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Collaborative R&D
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
  • 批准号:
    498310
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
  • 批准号:
    23K20339
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
  • 批准号:
    2740736
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
  • 批准号:
    2406592
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
  • 批准号:
    2305890
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
  • 批准号:
    23K20355
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
  • 批准号:
    23K24782
  • 财政年份:
    2024
  • 资助金额:
    $ 135.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了