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.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的神经退行性疾病，发病率超过 6.5 目前有 100 万美国人患有 AD 痴呆症，其定义是其神经病理学特征。 标志包括 Aβ 肽斑块沉积、神经元内 tau 蛋白缠结和神经元损失。 AD 过程的一个主要组成部分是全基因组关联研究。 （GWAS）揭示了几种免疫基因，这些基因是发展迟发性疾病的危险因素 AD 中的一些 AD 风险基因（例如 SPI1 和 TREM2）在小胶质细胞中高度表达， 大脑中常驻的巨噬细胞样群吞噬 Aβ 并发挥核心作用。 在大脑对淀粉样斑块和神经退行性过程的反应中。 干细胞衍生的神经类器官通常不包含免疫细胞群，干细胞 Pharm 的水凝胶神经类器官可以将小胶质细胞纳入可重复的、 我们初步采用适合筛选应用的 96 孔板形式。 数据表明小胶质细胞融入神经类器官并对 包括 Aβ 寡聚物和凋亡神经元在内的炎症刺激将导致该提案的工作。 通过将培养物暴露于 寡聚 Aβ 和凋亡神经元细胞诱导 AD 样神经炎症反应， 最终为药物发现应用提供更具生物学相关性的人类 AD 模型 重点关注免疫调节。具体目标将1）优化模型并建立基因。 2) 并整合经过改造的小胶质细胞的突变 AD相关基因TREM2的完成将建立一个灵活的目标。 能够筛选效应化合物或掺入的神经炎症模型系统 含有突变 AD 相关基因的小胶质细胞的 II 期研究将寻求扩大这一范围。 通过建立和优化读数来测量模型的功能 神经元细胞群的炎症并从其他供体中建立类器官。 最终，这项工作将开发商业化的新型 AD 炎症模型 该过程可以补充目前可用的许多啮齿动物模型系统。