Probing Heterogeneity of Alzheimer's disease using iPSCs

使用 iPSC 探索阿尔茨海默病的异质性

基本信息

批准号：
9923549
负责人：
Tracy L YOUNG-PEARSE
金额：
$ 52.46万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923549
关键词：
Address Adult Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Astrocytes Autopsy Brain Brain Pathology Categories Cell Line Cell model Cells Cellular Assay Cerebral cortex Cleaved cell Clinical Clinical Data Clinical Trials Coculture Techniques Cognition Cognitive Coupled Data Data Set Degenerative Disorder Dementia Deterioration Diagnostic Disease Early Intervention Early intervention trials Enzyme-Linked Immunosorbent Assay Enzymes Etiology Functional disorder Funding Agency Generations Genes Genetic Goals Heterogeneity Human INPPL1 gene Impaired cognition In Vitro Individual Inherited Inositol Intervention Late Onset Alzheimer Disease Location Maps Measurement Measures Memory Memory Loss Methods Microglia Missense Mutation Modeling Molecular Molecular Profiling Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Outcome Pathogenesis Pathologic Pathologist Pathology Pathway Analysis Pathway interactions Peptide Hydrolases Phenotype Phosphoric Monoester Hydrolases Play Predisposition Presenile Alzheimer Dementia Prosencephalon Protein Precursors Proteome Proteomics Risk Risk Factors Role Senile Plaques Series Signal Pathway Statistical Models Study Subject Subgroup Susceptibility Gene System Systems Biology Tauopathies Testing Therapeutic Intervention Treatment Efficacy Western Blotting aged brain cell brain tissue chemokine cohort comorbidity cytokine early detection biomarkers early onset extracellular familial Alzheimer disease genome wide association study glial activation human subject hyperphosphorylated tau improved induced pluripotent stem cell inositol-1,4,5-trisphosphate 5-phosphatase neuropathology neurotoxic novel patient population patient subsets phosphoinositide-3,4,5-triphosphate phosphoinositide-3,4-bisphosphate predictive marker presenilin prognostic tool religious order study stem cell technology stem cells symptom management targeted treatment tau Proteins tau-1 therapeutic development transcriptome transcriptome sequencing transcriptomics

项目摘要

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by dysfunction and deterioration of neurons resulting in loss of memory and progressive cognitive decline. Current treatments are aimed only at symptom management. Three barriers to effective therapeutic development include: 1) a lack of definition of the heterogeneity of AD pathogenesis, 2) a lack of highly predictive biomarkers to facilitate early intervention, and 3) a need to identify pathways involved in cognitive decline and AD that can be targeted for therapeutic intervention. We are using induced pluripotent stem cell (iPSC) technology coupled to comprehensive studies of patient populations to interrogate the cellular and molecular mechanisms underlying AD in an effort to break down these barriers. We propose that there exist multiple forms of AD that have different underlying causes, and that multiple therapeutic interventions may be needed to address disparate etiologies. Through other funding sources, we have generated 50 iPSC lines from two cohorts, the Religious Order Study (ROS) and the Memory and Aging Project (MAP). Here, we propose to study these lines, where we focus upon three categories of subjects that lie on the extreme ends of the pathological spectrum: 1) no brain pathology, not cognitively impaired, 2) high pathology not cognitively impaired, and 3) high pathology, late onset Alzheimer’s disease. In addition, we have generated and/or collected iPSC lines from familial AD subjects, which will be analyzed in parallel. Using iPSC derived neurons, astrocytes, and microglia from 60 human subjects, we will measure AD relevant outcomes (Aβ, p-tau, cytokines/chemokines) in Aim 1 and acquire unbiased transcriptomic and proteomic data in Aim 2. These data will be integrated with clinical data, neuropathology data, and genetic data acquired from the same subjects from whom the cells were derived using multiple computational approaches. We hypothesize that: 1) Some pathological findings in the postmortem brain can be predicted by in vitro cellular assays on iPSC derived neurons and glia (Aim 1), and 2) Both neuropathology and cognitive decline in some human subjects can be predicted by transcriptomic and proteomic level network analyses of iPSC derived neurons and glia. Preliminary data from 12 lines supports the premise that iPSC-derived cells will capture certain cell and molecular signatures that define subgroups of aged adults. Data from all 50 ROS/MAP lines and EOAD models generated in aims 1 and 2 will provide a well-defined framework to address mechanistic questions regarding AD. In Aim 3 we will leverage the deeply characterized set of iPSC-derived cultures to address the hypothesis that dysregulated inositol 5-phosphatase activity of INPP5D (SHIP1) and/or INPPL1 (SHIP2) leads to an elevated risk for LOAD in a subset of subjects. Through these studies, we aim to evaluate whether iPSC- derived cells can act as a diagnostic or prognostic tool for cognitive decline and AD, and begin to address the cell and molecular mechanisms underlying heterogeneity in LOAD.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是神经功能障碍和恶化目前的治疗仅针对导致记忆丧失和进行性认知能力下降的神经元。有效治疗开发的三个障碍包括：1）缺乏对症状的定义。 AD 发病机制的异质性，2) 缺乏高度预测性的生物标志物来促进早期干预，以及 3) 需要确定与认知衰退和 AD 相关的途径，以作为治疗的目标。我们正在使用诱导多能干细胞（iPSC）技术与综合研究相结合。患者群体探究 AD 背后的细胞和分子机制，以努力打破我们认为存在多种形式的AD，它们具有不同的根本原因，并且可能需要通过其他资助采取多种治疗干预措施来解决不同的病因。根据消息来源，我们从宗教秩序研究 (ROS) 和记忆研究这两个队列中生成了 50 个 iPSC 系。在这里，我们建议研究这些线路，其中我们重点关注三类：处于病理谱极端的受试者：1）没有大脑病理学，没有认知学病理学受损，2) 高度病理，无认知障碍，以及 3) 高度病理，迟发性阿尔茨海默氏病。此外，我们还从家族性 AD 受试者中生成和/或收集了 iPSC 系，这些系将在我们将使用来自 60 名人类受试者的 iPSC 衍生的神经元、星形胶质细胞和小胶质细胞来测量 AD。目标 1 中的相关结果（Aβ、p-tau、细胞因子/趋化因子）并获得公正的转录组学和目标 2 中的蛋白质组数据。这些数据将与临床数据、神经病理学数据和遗传数据整合使用多种计算方法从细胞来源的同一受试者获得。我们假设：1）死后大脑中的一些病理结果可以通过体外细胞来预测。对 iPSC 衍生的神经元和神经胶质细胞进行检测（目标 1），以及 2）某些患者的神经病理学和认知能力下降可以通过 iPSC 衍生的转录组和蛋白质组水平网络分析来预测人类受试者来自 12 个细胞系的初步数据支持 iPSC 衍生细胞将捕获某些特定的假设。定义老年人亚组的细胞和分子特征来自所有 50 个 ROS/MAP 系和 EOAD。目标 1 和 2 生成的模型将为解决机械问题提供明确的框架在目标 3 中，我们将利用一系列经过深入表征的 iPSC 衍生培养物来解决 AD 问题。假设 INPP5D (SHIP1) 和/或 INPPL1 (SHIP2) 的肌醇 5-磷酸酶活性失调导致。通过这些研究，我们旨在评估 iPSC 是否会导致部分受试者的 LOAD 风险升高。衍生细胞可以作为认知衰退和 AD 的诊断或预后工具，并开始解决 LOAD 异质性背后的细胞和分子机制。