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
• 负责人: ARON S BUCHMAN
• 金额: $ 71.13万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920077
• 关键词: Accounting; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; American; Area; Automobile Driving; Autopsy; Biology; Brain; Brain Pathology; Central Nervous System Diseases; Cerebrovascular Disorders; Cessation of life; Clinical; Cognition; Cognitive; Cohort Studies; Contralateral; Data; Dementia; Disease; Educational workshop; Elderly; Female; Future; Gait; Gait speed; Gene Expression; Gene Proteins; Genes; Health; Histopathology; Impairment; Individual; Influentials; Knowledge; Lewy Bodies; Measures; Memory; Methods; Molecular; Monitor; Motor; Muscle; Participant; Pathologic; Pathology; Peripheral; Persons; Phenotype; Pilot Projects; Proteins; Public Health; Reaction; Research; Research Personnel; Resources; Signal Transduction; Specimen; Spinal Cord; System; Systems Biology; Testing; Tissue Sample; Tissues; Validation; Ventral Horn of the Spinal Cord; Work; base; cell growth regulation; differential expression; disease phenotype; genome-wide; impaired driving performance; instrument; male; new therapeutic target; novel; quadriceps muscle; transcriptome sequencing; transcriptomics; wearable sensor technology

ABSTRACT Responding to PAR 17-029: Dynamic Interactions between systemic or non-neuronal systems and the brain in aging and in AD, this study will identify the molecular mechanisms driving impaired mobility, an understudied aging and AD phenotype, as highlighted by NIA workshops, Aging, the CNS, and Mobility. AD and other brain pathologies are related to impaired mobility in older adults with and without dementia, but do not fully explain impaired mobility. These pathologies extend beyond the brain to spinal cord, but even accounting for these pathologies does not fully explain mobility and the molecular drivers of these pathologies are unknown. This suggests that there are also drivers without a pathologic footprint that remain unidentified in these tissues. Mobility derives from interacting subsystems that extend beyond the brain to spinal cord and muscle. Therefore, this postmortem study in older adults will identify molecular drivers (genes and their proteins) of impaired mobility in key mobility tissues controlling for the presence of AD and other CNS pathologies. This study will leverage clinical and postmortem resources from older participants of the Rush Memory and Aging Project (R01AG17917). Our systems biology approach will be applied to new gene expression data obtained from key mobility tissues in brain, spinal cord and muscle (Aim1). Tissues will come from the same persons, all of whom had instrumented gait testing with a wearable sensor proximate to death. In each tissue, we will identify mobility-related molecular systems controlling for CNS pathologies (Aim2). Causal network inference will be used to nominate influential genes controlling these systems (Aim3). Validating protein levels of influential genes within and across these tissues will yield a high-confidence list of genes driving impaired mobility (Aim4). Compelling pilot studies support this proposal. 1) Combinations of wearable sensor mobility metrics are more specific for AD dementia than conventional gait speed. 2) AD and other pathologies extend to spinal cord and are related to mobility, emphasizing the need to identify drivers of these pathologies in motor tissues outside the brain. 3) Also, the limited explanatory power of CNS pathologies for mobility highlights the need to identify molecular drivers of impaired mobility in key motor tissues that may not have a known pathologic footprint. 4) High quality genome-wide transcriptomic data extracted from key motor tissues show differentially expressed genes are related to gait, cognition and AD pathology. 5) Applying the system biology methods to a cortical cognitive gene network, followed by validation with protein, we identified cortical proteins driving cognition. Leveraging broad expertise, this study will provide an in-depth description of the molecular drivers within interconnected subsystems underlying mobility within and outside the CNS. Validating influential genes provides a means to move beyond a descriptive study by providing novel therapeutic targets. This study has potential to make a sustained impact on aging research, inform on efforts to maintain ambulation and reduce a major adverse health consequence of aging and AD.

抽象的 响应 PAR 17-029：系统或非神经元系统与大脑之间的动态相互作用 衰老和 AD 方面，这项研究将确定导致行动能力受损的分子机制，这是一个尚未得到充分研究的问题 衰老和 AD 表型，正如 NIA 研讨会“衰老、中枢神经系统和移动性”所强调的那样。 AD和其他大脑 病理与患有或不患有痴呆症的老年人的活动能力受损有关，但不能完全解释 行动不便。这些病变从大脑延伸到​​脊髓，但即使解释了这些 病理学并不能完全解释流动性，并且这些病理学的分子驱动因素尚不清楚。这 表明这些组织中还存在一些没有病理足迹但仍未被识别的驱动因素。 移动性源自从大脑延伸到​​脊髓和肌肉的相互作用的子系统。 因此，这项针对老年人的尸检研究将确定分子驱动因素（基因及其 控制AD和其他中枢神经系统存在的关键活动组织中活动受损的蛋白质） 病理学。这项研究将利用 Rush 年长参与者的临床和尸检资源 记忆与衰老项目（R01AG17917）。我们的系统生物学方法将应用于新基因 从大脑、脊髓和肌肉的关键活动组织中获得的表达数据（Aim1）。纸巾会来的 来自同一个人，他们都在临死前用可穿戴传感器进行了步态测试。 在每个组织中，我们将识别控制中枢神经系统病理的与运动相关的分子系统（目标2）。 因果网络推理将用于提名控制这些系统的有影响力的基因（目标3）。 验证这些组织内部和之间有影响的基因的蛋白质水平将产生一个高可信度的列表 导致行动能力受损的基因（Aim4）。令人信服的试点研究支持了这一提议。 1) 组合 可穿戴传感器移动性指标比传统步态速度更适合 AD 痴呆症。 2) 广告和 其他病变延伸至脊髓并与活动能力相关，强调需要确定驱动因素 这些病变发生在大脑外部的运动组织中。 3）此外，中枢神经系统病理学的解释力有限 流动性强调需要确定关键运动组织中流动性受损的分子驱动因素，这可能 没有已知的病理足迹。 4) 从关键基因中提取的高质量全基因组转录组数据 运动组织显示差异表达基因与步态、认知和 AD 病理有关。 5) 申请 皮层认知基因网络的系统生物学方法，然后用蛋白质进行验证，我们 确定了驱动认知的皮质蛋白。本研究将利用广泛的专业知识，提供深入的研究 互连子系统内分子驱动因素的描述，这些子系统是内部和外部流动性的基础 中枢神经系统。验证有影响力的基因提供了一种超越描述性研究的方法，提供新颖的研究 治疗目标。这项研究有可能对衰老研究产生持续影响，并为以下方面的努力提供信息： 保持行走并减少衰老和 AD 对健康的重大不利后果。