CAREER: Cellular reprogramming to transform human fibroblasts into diverse and specific neuronal subtypes

1454508Colby, David W.这个职业项目将寻找方法，将容易从活人身上获得的细胞类型转化为神经元，这种细胞类型在活人的大脑中通过活组织检查获得是危险的。活体人类神经元的来源需要用作模型系统，用于研究和发现阿尔茨海默氏症等神经系统疾病的治疗方法，促进脑机接口的发展，使盲人能够看到东西，使残疾士兵能够在精神上控制假肢，或者通过互联网直接从一个大脑到另一个大脑，以“心灵感应”的方式在世界各地发送思想。该项目将开发利用基因工程方法快速、高产量地获得特定神经元亚型的方法，这些方法已在医学界得到认可，从而大大加快了医学和技术领域的进展速度。研究团队还致力于教育公众关于生物工程研究的重要性，并激励下一代研究人员。在夏季的几个月里，一位来自特拉华州威尔明顿的当地公立高中教师将沉浸在研究环境中，因为他们准备了一门高中水平的课程，向学生介绍生物工程。最近的研究进展使人们能够将常见的人类细胞类型（如皮肤细胞和血细胞）重新编程为干细胞、神经元和其他更难获得的细胞。这种转化的细胞最终可能会用于基于细胞的治疗，并且已经被用于人类疾病的体外模型，可以用来衍生更传统的治疗方法。然而，细胞重编程领域在生成组成大脑的数百种不同的神经元亚型方面取得的进展有限，阻碍了神经科学和神经疾病研究的进展。该项目的目标是设计一种高通量的方法来鉴定能够进行所需细胞反式分化的转录因子。研究小组将把这种方法应用于成纤维细胞重编程成特定的神经亚型。改变指导和维持细胞特性的特定转录因子的表达水平是细胞重编程最成功的方法。研究小组将创建一个与神经发育相关的转录因子文库，并对文库进行筛选，以确定能够将人类成纤维细胞转化为两种特定神经元亚型的因子，表征其功能，并迭代应用该过程以增强功能和产量；这种方法在蛋白质工程领域取得了巨大的成功。

1454508Colby, David W. This CAREER project will identify approaches to transform easily obtainable cell types from living people into neurons, which are dangerous to obtain by biopsy of the brain in living humans. Sources of live human neurons are needed for use as model systems to study and to discover cures for neurological diseases such as Alzheimer's, to facilitate the development of brain-machine interfaces for enabling the blind to see, enable disabled soldiers to mentally control prosthetic limbs or to send thoughts 'telepathically' across the world, directly from brain to brain over the internet. This project will develop approaches to derive specific neuronal subtypes rapidly and in high yield using genetic engineering approaches which have gained acceptance within the medical community, thereby broadly accelerating the rate of progress across both medical and technological fields. The research team is also committed to educating the public about the importance of Bioengineering research and inspiring the next generation of researchers. During the summer months, a local public high school teacher from Wilmington, DE, will be immersed in the research environment as they prepare a high school level course that will introduce students to Bioengineering. Recent research advances have enabled the ability to reprogram commonly available human cell types, like skin and blood cells, into stem cells, neurons, and other cells that are more difficult to obtain. Such transformed cells may eventually be useful for cell-based therapies, and are already finding use as in vitro models of human disease, which can be used to derive more conventional therapies. However, the field of cellular reprogramming has made limited progress toward generating the hundreds of different neuronal subtypes that make up the brain, impeding progress in neuroscience and neurological disease research alike. The objective of this project is to design a high throughput approach for the identification of transcription factors capable of carrying out desired cellular trans-differentiations. The research team will apply this approach to the reprogramming of fibroblasts into specific neural subtypes. Altering expression levels of specific transcription factors that direct and maintain cell identity has been the most successful approach for cellular reprogramming. The research team will create a library of transcription factors associated with neural development and screen the library to identify factors that can transform human fibroblast cells into two specific neuronal subtypes, characterize their function, and iteratively apply the process for enhanced function and yield; this approach has been highly successful in the field of protein engineering.