# Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration

> **NIH NIH R01** · MARQUETTE UNIVERSITY · 2021 · $379,626

## Abstract

PROJECT SUMMARY
In adults, axons in the central nervous system (CNS) generally fail to regenerate after they are lost to injury or
disease, leading to permanent and incurable disability. Axon growth is prevented by a hostile growth environment,
as well as a developmental loss in the intrinsic capacity for axon growth as CNS neurons age. Transcription
factors (TFs) interact with DNA and coordinate the production of broad sets of cellular materials, and have
emerged as important therapeutic targets to boost regenerative ability within injured neurons. For example, forced
re-expression of a pro-regenerative TF called KLF6 in adult neurons can improve their capacity for axon growth
after spinal injury. We will now test three complementary and mutually supportive strategies to enhance the
promising pro-regenerative properties of KLF6. First, using a novel bioinformatics pipeline, we have predicted
additional TFs that functionally interact with KLF6 and verified their ability to synergistically enhance axon growth
when combined with KLF6 in cell culture models of axon growth. We will therefore perform in vivo tests of three
selected factors, EOMES, NR5A2, and RARB, for the ability to enhance KLF6’s pro-regenerative properties in
animal models of spinal cord injury. Second, we will supplement these TF interventions with transplants of growth-
permissive stem cells into sites of spinal injury. These grafts will alleviate persistent growth inhibition in the spinal
cord environment, and thus unmask the pro-regenerative effects of TF treatments. Finally, we will harness a newly
developed gene therapy vector that enables retrograde delivery of genes with unprecedented efficiency. Injection
of this vector to the spinal cord results in widespread gene expression in injured neurons throughout the
brainstem, midbrain, and motor cortex. This delivery system engages a larger number and a wider diversity of
cell types than the current practice of direct brain injection, thus maximizing the chance of achieving functional
gains after spinal injury. Throughout these aims, tissue clearing and 3D microscopy will reveal new anatomical
details of the evoked regeneration. Bringing together these cutting-edge improvements to a TF-centered strategy
will move the field toward novel and effective treatments for individuals suffering from the debilitating
consequences of CNS injury.

## Key facts

- **NIH application ID:** 10126914
- **Project number:** 5R01NS083983-08
- **Recipient organization:** MARQUETTE UNIVERSITY
- **Principal Investigator:** Murray G Blackmore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $379,626
- **Award type:** 5
- **Project period:** 2013-07-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126914

## Citation

> US National Institutes of Health, RePORTER application 10126914, Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration (5R01NS083983-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10126914. Licensed CC0.

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