Rewiring gene regulatory circuits to enhance central nervous system repair

Introduction

The mammalian central nervous system (CNS) is the epitome of complex cellular architecture. Still, it has a limited capacity to self-repair after an injury, which contrasts with the regenerative potential of the CNS in lower vertebrates. Regeneration unfolds by the orchestrated triggering of developmental gene expression programs after injury.

Regenerative Mechanisms

These programs are under the control of dedicated regeneration enhancer elements, which grant adult cells transcriptional access to developmental genes. Neural stem cells in the mammalian CNS lack the gene regulatory circuits that dictate when and where to activate the expression of developmental genes for regeneration. Consequently, most of the cells lost to injury are never replaced.

Proposal Objectives

This proposal aims to rewire mammalian gene expression circuits to endow neural stem cells with the capacity to activate regenerative responses after injury.

Methodology

1. Identification of Enhancer Elements
   Building on innovative technologies, some of which I developed, we will identify injury-responsive enhancer elements in the mouse spinal cord with single cell and spatiotemporal resolution.

2. Decoding Injury-Sensing DNA Elements
   Using machine learning, we will decode the rules of injury-sensing DNA elements to design synthetic injury-responsive enhancers for precise gene expression control in neural stem cells.

3. Therapeutic Application
   Finally, we will use synthetic enhancers in therapeutically relevant gene delivery systems to rewire gene circuits in order to promote the recruitment of resident stem cells for cell replacement through the reactivation of developmental genes that would otherwise remain silent.

Expected Outcomes

The proposed research will uncover basic principles of gene regulation after CNS injury and open new avenues for the design of smart gene therapies for regenerative medicine using synthetic regeneration enhancers.