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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：
10400951
负责人：
Tracy L YOUNG-PEARSE
金额：
$ 48.93万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400951
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 Clinical Clinical Data Clinical Trials Coculture Techniques Cognition Cognitive Coupled Data Data Set Degenerative Disorder Dementia Deterioration Disease Early Intervention Early Onset Alzheimer Disease 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 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 diagnostic tool 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.

阿尔茨海默病（Alzheimer 's disease， AD）是一种神经退行性疾病，其特征是神经功能障碍和神经退化