Direct Conversion of Human Fibroblasts into Neuronal Cells by Small Molecules (hCiN)

合法和非法药物的使用给国家的医疗保健系统带来了巨大的负担， 经济，每年花费超过5000亿美元。成瘾是一种慢性大脑 一种导致对毒品的强迫性欲望的疾病，尽管对人体有害 后果，包括对健康的直接影响以及对社会的危害， 包括家庭解体、虐待儿童、失业以及各种各样的 犯罪。重新编程人类体细胞以改变细胞身份具有巨大的 神经疾病建模、高通量药物筛选、细胞治疗 和个性化医疗。然而，在患者特异性治疗之前仍然存在一些挑战。 通过重新编程产生的细胞可以提供对神经疾病的可靠见解 机构（例如，药物滥用/成瘾，其他神经系统疾病）或有效 应用于药物发现和移植治疗。使用我们的创新专利 人工三维微环境生态位构建技术与森林筛选 重编程小分子（美国专利#9045737），我们已经开发了一种 初步的小分子混合物，有效地（高达50%的起始细胞数， 主要是谷氨酸能神经元）并直接将人成纤维细胞转化为神经元， 绕过神经祖细胞阶段（化学诱导的神经元，hCiN）。在这 第一阶段的建议，我们试图证明这种方法的可行性， 优化我们的初步hCiN鸡尾酒，同时研究hCiN功能与 分子、细胞、电生理测定和小鼠脑移植 模型

Licit and illicit drug use places a large burden on the nation's health care systems and the economy, costing more than $500 billion annually. Addiction is a chronic brain disease that leads to a compulsive desire for drugs despite significantly harmful consequences, including direct effects on health as well as detriments to society, including disintegration of families, child abuse, loss of employment, and a broad array of crimes. Reprogramming of human somatic cells to alter cellular identity has enormous potential for neurological disease modeling, high-throughput drug screening, cell therapy, and personalized medicine. However, several challenges remain before patient-specific cells produced by reprogramming can provide reliable insights into neurological disease mechanisms (e.g., Drug abuse/ addiction, other neurological disorders) or be efficiently applied to drug discovery and transplantation therapy. Using our innovative patented technology to develop Artificial 3D Microenvironment Niche and screen for reprogramming small molecules (US Patent # 9045737), we have developed a preliminary small molecule cocktail that efficiently (up to 50% of starting cell numbers, mostly Glutamatergic Neurons) and directly converts human fibroblasts into neurons, bypassing the neural progenitor stage (Chemically induced Neurons, hCiN). In this Phase I proposal, we attempt to demonstrate the feasibility of this methodology by optimizing our preliminary hCiN cocktails while investigating hCiN functionally with molecular, cellular, electrophysiological assays and in a mouse brain transplantation model.