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

基本信息

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
项目类别：
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&apos 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

项目摘要

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/摘要神经和精神疾病，包括阿尔茨海默氏病（AD），发挥了毁灭性的个人对患者，家庭，护理人员和社会的经济损失。有效的药物，反映的药物发现了与目标疾病无关的发现平台人类最近开发的诱导干细胞（IPSC）使得筛查和验证包括患者在内的人类细胞上的候选化合物，因此可能增加 CNS药物开发的成功率和加速速度。 Brainxell，Inc。率先开发了CNS Drugg的人类患者脑细胞平台发现。 IPSC通过我们的平台技术进行定向区分和扩展忠实的祖细胞的扩展。但是，IPSC衍生的小胶质细胞不成熟，与胎儿阶段相当，这使它成为Difficalt 用于介绍疾病表型和用于药物铅的高促进筛查（HTS） Thase I Sbir项目的目标是Touncover分子的速度在IPSC衍生的小胶质细胞中具有成熟状态的Genessect的表达，并制定鸡尾酒在电镀后1-3周内产生成熟的小胶质细胞。纳米酸酯酶（NLUC）融合到P2RY12，这是一种在成熟的小胶质细胞中的嘌呤能受体启用并简化筛选小分子以加速小胶质细胞成熟。快速产生成熟的人类小胶质细胞的有效鸡尾酒将消除建立的主要障碍人类患者小胶质细胞基于CNS药物开发的HTS。