Engineering regeneration in the central nervous system

Our central nervous system (CNS) contains an astounding number and diversity of neurons that are generated during embryonic development.

Embryonic progenitors unfold specific genetic programs through the activity of particular sets of transcription factors to generate neuron diversity. Some embryonic progenitors then transform into adult stem cells. During this process, adult stem cells lose the expression of neurogenic factors and cease to generate neurons.

Consequently, neurons lost to injury or disease are never replaced leading to long-term functional impairment.

Reactivating developmental gene expression programs in adult tissues is a central goal of regenerative medicine.Here I propose to harness the power of single cell genomics to identify the molecular programs that drive neuron subtype specific neurogenesis in the embryonic spinal cord. Then, I will identify candidates for reactivation through comparative genomic analysis with adult neural stem cells.

I will then perform a single-cell CRISPR-activation screen using therapeutically relevant gene-delivery vectors to identify factors that elicit neurogenesis in vivo among the identified candidates.

The functional relevance of the newly generated neurons will be tested in mouse models of spinal cord injury and amyotrophic lateral sclerosis.

This study will set the ground for a new generation of regenerative medicine strategies using molecular engineering in the regeneration-recalcitrant mammalian CNS.