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：
10159823
负责人：
Tracy L YOUNG-PEARSE
金额：
$ 48.92万
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/10159823
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 Induced pluripotent stem cell derived neurons 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 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 induced pluripotent stem cell technology 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 cells symptom management targeted treatment tau Proteins tau-1 therapeutic development therapeutically effective 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.

阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征是功能障碍和恶化神经元导致记忆力下降和渐进认知能力下降。目前的治疗仅针对症状管理。有效治疗发展的三个障碍包括：1）缺乏对 AD发病机理的异质性，2）高度预测性生物标志物缺乏促进早期干预和 3）需要确定可以针对治疗的认知下降和AD的途径干涉。我们正在使用诱导的多能干细胞（IPSC）技术，该技术与对患者种群询问AD的细胞和分子机制，以打破在这些障碍物上。我们建议存在多种形式的AD，它们具有不同的基本原因，并且可能需要进行多种治疗干预措施来解决不同的病因。通过其他资金消息来源，我们已经从两个同伙，宗教秩序研究（ROS）和记忆中产生了50条IPSC线和老化项目（地图）。在这里，我们建议研究这些线，我们将重点放在三类位于病理谱系极端的受试者：1）没有脑病理学，不是认知上的受损害，2）高病理学不认知障碍，3）高病理学，晚期发作的阿尔茨海默氏病。在此外，我们已经从家族广告受试者中生成和/或收集了IPSC线，将在其中分析平行线。使用来自60名人类受试者的IPSC衍生神经元，星形胶质细胞和小胶质细胞，我们将测量AD AIM 1中的相关结果（Aβ，P-TAU，细胞因子/趋化因子），并获得无偏的转录组和 AIM 2中的蛋白质组学数据。这些数据将与临床数据，神经病理学数据和遗传数据集成从使用多种计算方法得出细胞的同一受试者中获得。我们假设：1）可以通过体外细胞来预测死后大脑中的一些病理发现对IPSC衍生神经元和神经胶质的测定（AIM 1），以及2）神经病理学和认知能力下降可以通过IPSC的转录组和蛋白质组学水平网络分析来预测人类受试者神经元和神经胶质。来自12行的初步数据支持IPSC衍生的单元格的前提定义老年人亚组的细胞和分子特征。来自所有50个ROS/MAP线和EOAD的数据目标1和2中产生的模型将提供一个定义明确的框架来解决机械问题关于广告。在AIM 3中，我们将利用深层特征的IPSC衍生文化来解决假设Inpp5d（Ship1）和/或Inppl1（Ship2）的肌醇5-磷酸酶活性的非调节词在受试者子集中承受负荷的风险升高。通过这些研究，我们旨在评估IPSC-是否是否衍生细胞可以充当认知下降和AD的诊断或预后工具，并开始解决载荷中异质性的细胞和分子机制。