Accelerating Functional Maturation of Human iPSC-Derived Microglia

加速人 iPSC 衍生的小胶质细胞的功能成熟

• 批准号: 10259242
• 负责人: Zhong-wei Du
• 金额: $ 25.52万
• 依托单位: BRAINXELL, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259242
• 关键词: Adult; Alzheimer' s Disease; Biological Assay; Brain; Cell Line; Cells; Cellular Morphology; Central Nervous System Diseases; Clinical Trials; Communities; Development; Dimethyl Sulfoxide; Disease; Drug Screening; Economics; Engineering; Event; Exhibits; Failure; Family Caregiver; Formulation; Functional disorder; Gene Expression; Gene Expression Profile; Goals; Human; Immune; Libraries; Luciferases; Mental disorders; Microglia; Modeling; Morphology; Neurodegenerative Disorders; Pathologic; Patients; Performance; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Process; Promega; Purinoceptor; Reporter; Research; Small Business Innovation Research Grant; Societies; Speed; Techniques; Technology; Testing; Therapeutic; Time; Validation; base; brain cell; cell immortalization; disease phenotype; drug development; drug discovery; fetal; high throughput screening; high-throughput drug screening; human disease; human pluripotent stem cell; human stem cells; induced pluripotent stem cell; nanoluciferase; nervous system disorder; neurotransmission; novel therapeutics; postnatal human; progenitor; screening; small molecule; success

Project Summary/Abstract Neurological and psychiatric disorders, including Alzheimer’s disease (AD), exert a devastating personal and economic toll on patients, families, caregivers, and society. This is in part due to our failure to develop effective medications, reflecting drug discovery platforms that are often not relevant to target diseases. The recent development of induced pluripotent stem cells (iPSCs) from humans makes it possible to screen and validate candidate compounds on human brain cells, including those from patients, thus potentially increasing the success rate and speeding the pace of CNS drug development. BrainXell, Inc. has pioneered the development of human patient brain cell-based platforms for CNS drug discovery. We are able to produce large quantities of highly enriched microglia of consistent quality from human iPSCs through our platform technology of directed differentiation and expansion of committed progenitors. However, iPSC-derived microglia are immature, comparable to those at the fetal stage, which makes it difficult for presentation of disease phenotypes and for high-throughput screening (HTS) for drug leads intended for those whose brains are fully mature. The goal of this Phase I SBIR project is to uncover molecules that speed the expression of genes associated with a mature state in iPSC-derived microglia and to formulate cocktails that yield mature microglia within 1-3 weeks after plating. We will engineer a human iPSC reporter line with nanoluciferase (Nluc) fused to P2RY12, a purinergic receptor highly expressed in mature microglia. This line will enable and simplify the screening of small molecules for accelerating microglia maturation. Formulation of an effective cocktail for rapidly generating mature human microglia will remove a major roadblock in establishing human patient microglia-based HTS for CNS drug development.

项目摘要/摘要 神经和精神障碍，包括阿尔茨海默病(AD)，对个人造成毁灭性的影响 以及给患者、家庭、照顾者和社会带来的经济损失。这在一定程度上是由于我们没有发展起来。 有效的药物，反映出药物发现平台往往与目标疾病无关。这个 人类诱导多能干细胞(IPSCs)的最新发展使筛选和 验证人类脑细胞上的候选化合物，包括来自患者的化合物，从而潜在地增加 提高了中枢神经系统药物开发的成功率和速度。 BrainXell，Inc.率先开发了基于人类患者脑细胞的中枢神经系统药物平台 发现号。我们能够从人类体内大量产生质量稳定的高度浓缩的小胶质细胞。 IPSCs通过我们的平台技术定向分化和扩展致力于前辈。 然而，IPSC来源的小胶质细胞是不成熟的，与胎儿阶段的小胶质细胞相当，这使得研究变得困难 用于疾病表型的呈现和高通量筛选(HTS) 那些大脑完全成熟的人。这个第一阶段SBIR项目的目标是发现这种分子 与成熟状态相关的基因在IPSC来源的小胶质细胞中的表达和配制鸡尾酒 在接种后1-3周内产生成熟的小胶质细胞。我们将设计一条人类IPSC记者路线 纳米纤维素酶(Nluc)与在成熟小胶质细胞中高表达的嘌呤能受体P2RY12融合。这一行将 实现并简化小分子的筛选，以加速小胶质细胞的成熟。制定一项新的规则 快速产生成熟人小胶质细胞的有效鸡尾酒将消除建立 用于中枢神经系统药物开发的人患者小胶质细胞HTS。