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Human Neural Organoid Modeling of Alzheimer's Disease Neuroinflammation for Drug Discovery

阿尔茨海默病神经炎症的人类神经类器官模型用于药物发现

基本信息

批准号：
10758939
负责人：
Connie S Lebakken
金额：
$ 49.99万
依托单位：
STEM PHARM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758939
关键词：
3-Dimensional Abeta synthesis Adopted Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk American Amyloid beta-Protein Anti-Inflammatory Agents Antibodies Apoptotic Area Biological Biological Assay Biological Models Biology Brain Cells Control Groups Data Data Set Dementia Deposition Disease associated microglia Dose Engineering Functional disorder Gene Expression Gene Expression Profile Gene Targeting Generations Genes Genetic Transcription Gliosis Health Healthcare Human Hydrogels Immune In Vitro Inflammation Inflammation Process Inflammatory Label Late Onset Alzheimer Disease Macrophage Measures Microglia Modeling Morphology Mutation NCAM1 gene Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurofilament-L Neurons Organoids Outcome Patients Phagocytosis Pharmaceutical Preparations Phase Physiological Play Pluripotent Stem Cells Population Process Reproducibility Risk Factors Rodent Rodent Model Role Rosaniline Dyes SPI1 gene Sampling Senile Plaques Stimulant Stimulus System TREM2 gene Technology Testing Therapeutic Therapeutic Intervention Time Tissues Transgenic Organisms Work abeta accumulation abeta oligomer apolipoprotein E-3 biomarker identification cell type clinical predictors comparison control cost cytokine differential expression drug discovery experimental study flexibility genetic signature genome wide association study human model human stem cells immune modulating agents immunoregulation in vivo induced pluripotent stem cell meter mutant neural neuroinflammation neuron loss neuropathology new therapeutic target novel overexpression phase 2 study response risk variant screening single-cell RNA sequencing stem tau Proteins therapeutic evaluation transcription factor treatment group two-dimensional

项目摘要

Project Summary/Abstract Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease with more than 6.5 million Americans currently living with AD dementia. AD is defined by its neuropathological hallmarks which include Aβ peptide plaque deposits, intraneuronal tau tangles and neuronal loss. A major component of the AD process is neuroinflammation. Genome-wide association studies (GWAS) have revealed several immune genes which are risk factors for developing late-onset AD. Several of these AD risk genes such as SPI1 and TREM2 are highly expressed in microglia, the brain’s resident macrophage-like population. Microglia phagocytose Aβ and play a central role in the brain’s response to amyloid plaques and the neurodegenerative process. While pluripotent stem cell-derived neural organoids do not typically contain immune cell populations, Stem Pharm’s hydrogel-enabled neural organoids allow for incorporation of microglia in a reproducible, 96-well plate format amenable to screening applications. Using this technology, our preliminary data demonstrate microglia incorporate into the neural organoids and respond appropriately to inflammatory stimuli including Aβ oligomers and apoptotic neurons. Work in this proposal will lead to the generation of a human AD-neuroinflammation organoid model by exposing cultures with oligomeric Aβ and apoptotic neuronal cells to induce AD-like neuroinflammatory responses, ultimately enabling a more biologically relevant human AD model for drug discovery applications focused on immune modulation. Specific Aims will 1) optimize the model and establish the gene expression signature of the microglia; 2) and incorporate microglia engineered with mutations in the AD associated gene TREM2. Completion of these specific aims will establish a flexible neuroinflammation model system capable of screening the effects of compounds or incorporating microglia harboring mutant AD-associated genes. Phase II studies will seek to expand the capabilities of the model by establishing and optimizing readouts to measure the effect of inflammation on the neuronal cell populations and establish organoids from additional donors. Ultimately, this work will develop commercially available, novel models of the AD inflammation process which can serve to supplement the many rodent model systems currently available.

项目总结/文摘