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

University Of Delaware, Newark DE

Investigators

Abstract

1454508 Colby, 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.