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
• 负责人: ARON S BUCHMAN
• 金额: $ 66.33万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613427
• 关键词: Accounting; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; 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; Educational workshop; Elderly; Female; Future; Gait; Gait speed; Gene Expression; Genes; Health; Histopathology; Impairment; Individual; Influentials; Knowledge; Lewy Body Disease; 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; cell growth regulation; differential expression; disease phenotype; gene network; genome-wide; human old age (65+); 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：系统性或非神经系统与大脑之间的动态相互作用 衰老和AD中，这项研究将确定驱动迁移率受损的分子机制 NIA研讨会，老龄化，中枢神经系统和活动性强调了衰老和AD表型。广告和其他大脑 病理学与患有和没有痴呆的老年人的流动性受损有关，但不能完全解释 流动性受损。这些病理延伸到大脑到脊髓，甚至考虑到这些 病理不能完全解释迁移率，这些病理的分子驱动因素尚不清楚。这 表明还有一些没有病理足迹的驱动因素在这些组织中仍然不明。 移动性来自相互作用的子系统，这些子系统延伸到大脑到脊髓和肌肉。 因此，这项在老年人中的验尸研究将鉴定分子驱动因素（基因及其它们的驱动因素 蛋白质）在控制AD和其他CN的关键迁移率组织中的迁移率受损 病理。这项研究将利用Rush老年参与者的临床和验尸资源 内存和老化项目（R01AG17917）。我们的系统生物学方法将应用于新基因 从大脑，脊髓和肌肉中的关键迁移组织获得的表达数据（AIM1）。组织会来 来自同一个人，所有人都用可穿戴的传感器来进行步态测试。 在每个组织中，我们将确定控制CNS病理学的迁移率相关的分子系统（AIM2）。 因果网络推断将用于提名控制这些系统的影响基因（AIM3）。 验证这些组织内部和整个组织中有影响力基因的蛋白质水平将产生高信心的清单 驱动流动性受损的基因（AIM4）。引人入胜的试点研究支持这一建议。 1）组合 可穿戴传感器的迁移率指标比常规步态速度更具体。 2）广告和 其他病理扩展到脊髓，与移动性有关，强调需要识别驱动因素 这些病理在大脑外部运动组织中。 3）此外，CNS病理的有限解释能力 对于流动性，需要确定可能在关键运动组织中的分子驱动力的分子驱动力驱动力的驱动力驱动力 没有已知的病理足迹。 4）从密钥中提取的高质量全基因组转录组数据 运动组织显示出差异表达的基因与步态，认知和AD病理有关。 5）申请 皮质认知基因网络的系统生物学方法，然后用蛋白质验证，我们 鉴定出驱动认知的皮质蛋白。利用广泛的专业知识，这项研究将提供深入 描述内部和外部互连子系统中的分子驱动程序 中枢神经系统。验证有影响力的基因提供了一种通过提供新颖的方法来超越描述性研究的方法 治疗靶标。这项研究有可能对衰老研究产生持续影响，告知努力 保持行动，减少衰老和AD的重大不良健康后果。