Utilizing gene-level biomarkers of AD to identify pathophysiological mechanisms in human neurons

利用 AD 的基因水平生物标志物识别人类神经元的病理生理机制

• 批准号: 10727531
• 负责人: Judith Ann Potashkin
• 金额: $ 42.26万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727531
• 关键词: Acceleration; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Animal Model; Automobile Driving; Autophagocytosis; Bioenergetics; Bioinformatics; Biological Assay; Biological Markers; Biosensor; Cell physiology; Cells; Coupled; Data Set; Databases; Dementia; Depressed mood; Diagnosis; Disease; Electrophysiology (science); Endosomes; Epigenetic Process; Family; Fibroblasts; Functional disorder; Gene Expression; Generations; Genes; Glucose; Glutamates; Goals; Human; Impaired cognition; Impairment; Individual; Knowledge; Laboratories; Light; Link; Lysosomes; Memory Loss; Memory impairment; Meta-Analysis; Metabolic; Metabolic stress; Metabolism; Mitochondria; Mutation; Neurons; Neurophysiology - biologic function; Organelles; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Prevalence; Process; Production; Property; Proteins; Proteomics; Risk; Risk Factors; Signal Transduction; Societies; Synapses; System; Testing; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Work; cell type; clinically relevant; cognitive function; cohort; data repository; differential expression; disease phenotype; early detection biomarkers; familial Alzheimer disease; fluorescence imaging; gene network; genomic variation; glucose metabolism; healthy aging; high risk; high risk population; human disease; improved; innovation; insight; live cell imaging; memory encoding; neurophysiology; neurotransmission; novel therapeutics; optimism; protein aggregation; sex; stem cell biology; stem cell technology; synaptic function; tau Proteins; tool; transcriptomics; transmission process

Abstract Summary Recent advances AD therapeutics increases the urgency to identify individuals at risk for developing Alzheimer’s disease (AD). This effort can likely be accelerated using stem cell biology approaches which have led to the ability to generate human induced neurons (HiN) directly from easily obtainable patient cells such as fibroblasts. This serves as a powerful tool for studying aging and disease-related processes in clinically relevant cell types. Meta-analysis studies of existing transcriptomic databanks from AD patients and healthy individuals without dementia (nonAD) have also provided new insight into underlying pathophysiological drivers contributing to a diagnosis of AD. While these gene expression profiles have been identified for AD risk which carryover from the individual to their directly transformed neurons (human induced neuron, HiN). This is a crucial missing link needed to capture the physiological outcomes of these gene network profiles in order to identify associated mechanisms of metabolic stress, pathological protein aggregation and synaptic pathophysiology – all key features of AD. Therefore, we will apply neurophysiological and cellular functional analyses to HiNs derived from representative individuals diagnosed with sporadic or familial AD, as well as age/sex-matched nonAD controls, to identify functional consequences of these genomic variations in the human population. Our overall objective is to identify gene-pathway based biomarkers or risk factors for AD and define the neuronal pathophysiological phenotypes associated with these gene pathways. We will test the hypothesis that synaptic signaling, metabolism and protein handling processes in neurons derived from the AD population will reflect the alterations in gene pathways that distinguish healthy aging processes from AD pathogenesis, and thus can serve as important biomarkers. In Aim 1 we will identify mitochondrial functional deficits associated with alterations in glucose metabolism gene pathways in AD. In Aim 2 we will identify pathological manifestations of altered gene pathways regulating autophagy and protein mishandling in AD patients. In Aim 3 we will identify neurophysiological and synaptic signaling effects corresponding with altered gene networks in AD that underlie cognitive decline. The combination of our expertise in induced neuron production as well as bioinformatics and neurophysiology assays makes this a powerful and innovative proposal that will provide important insights into risk factors and biomarkers of AD. This comes at a crucial time in the AD field where it is imperative to identify at risk individuals early in order to maximize benefits of new therapeutics becoming available.

摘要摘要 AD 疗法的最新进展增加了识别有患 AD 风险的个体的紧迫性 使用干细胞生物学方法可能会加速阿尔茨海默病（AD）的进展。 导致能够直接从容易获得的患者细胞（例如 成纤维细胞是临床研究衰老和疾病相关过程的有力工具。 对 AD 患者和健康人的现有转录组数据库进行荟萃分析研究。 没有痴呆症（nonAD）的个体也为潜在的病理生理驱动因素提供了新的见解 虽然这些基因表达谱已被确定为 AD 风险，但有助于 AD 的诊断。 从个体到直接转化的神经元（人类诱导神经元，HiN）的残留。 捕获这些基因网络图谱的生理结果所需的关键缺失环节，以便 确定代谢应激、病理性蛋白质聚集和突触的相关机制 病理生理学——AD 的所有关键特征因此，我们将应用神经生理学和细胞功能学。 对诊断为散发性或家族性 AD 的代表性个体的 HiN 进行分析，以及 年龄/性别匹配的非 AD 对照，以确定这些基因组变异的功能后果 人口。 我们的总体目标是确定基于基因通路的 AD 生物标志物或风险因素，并定义 我们将检验与这些基因途径相关的神经元病理生理学表型。 AD 群体神经元中的突触信号传导、代谢和蛋白质处理过程 将反映区分健康衰老过程和 AD 发病机制的基因途径的变化， 因此可以作为重要的生物标志物，在目标 1 中，我们将识别线粒体功能缺陷。 在目标 2 中，我们将确定与 AD 中葡萄糖代谢基因途径的改变相关的基因。 AD 患者中调节自噬和蛋白质错误处理的基因途径改变的表现。 3 我们将识别与基因网络相对应的神经生理学和突触信号传导效应 AD 是认知衰退的基础，我们在诱导神经产生方面的专业知识相结合。 生物信息学和神经生理学测定使这是一个强大且创新的提案，它将提供 对 AD 风险因素和生物标志物的重要见解是在 AD 领域的关键时刻出现的。 必须及早识别处于危险中的个体，以便最大限度地发挥新疗法的益处 可用的。