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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' 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

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.

项目摘要/摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病，其发病率超过6.5 目前有100万美国人患有阿尔茨海默病。AD是由其神经病理定义的 特征包括Aβ多肽斑块沉积，神经元内tau缠结和神经元丢失。 AD过程的一个主要组成部分是神经炎症。全基因组关联研究 已经发现了几个免疫基因，它们是迟发性疾病的危险因素。 广告。其中几个AD风险基因，如SPI1和TREM2，在小胶质细胞中高表达， 大脑中常驻的巨噬细胞样群。小胶质细胞吞噬Aβ并发挥中心作用 在大脑对淀粉样斑块和神经退化过程的反应中。而多能性 干细胞衍生的神经有机体通常不包含免疫细胞群 制药公司的水凝胶激活的神经有机体允许将小胶质细胞掺入可复制的， 适用于筛分应用的96孔板格式。使用这项技术，我们初步的 数据显示，小胶质细胞整合到神经器官中，并对 炎性刺激，包括Aβ寡聚体和神经细胞凋亡。该提案中的工作将导致 人AD-神经炎性器官模型的建立 寡聚体Aβ和凋亡的神经细胞诱导AD样神经炎性反应 最终实现更具生物学相关性的人类AD模型用于药物发现应用 专注于免疫调节。特定的目标将1)优化模型并建立基因 小胶质细胞的表达特征；2)并整合有突变的小胶质细胞 AD相关基因TREM2。完成这些具体目标将建立灵活的 能够筛选化合物或掺入物影响的神经炎症模型系统 携带突变的AD相关基因的小胶质细胞。第二阶段研究将寻求扩大 通过建立和优化读数来衡量模型的效果 炎症对神经细胞群体的影响，并建立来自更多捐赠者的有机体。 最终，这项工作将开发出商业上可用的AD炎症的新模型 这一过程可以补充目前可用的许多啮齿动物模型系统。