Decoding the regulatory genome of CNS regeneration
- Reference number
- IS24-0008
- Project leader
- Llorens Bobadilla, Enric
- Start and end dates
- 241101-271231
- Amount granted
- 4 900 000 SEK
- Administrative organization
- Karolinska Institutet
- Research area
- Life Sciences
Summary
The adult central nervous system (CNS) of most mammals, including humans, has a limited capacity to self-repair and injuries lead to scar formation and long-term functional deficits. This regeneration failure underlies the significant socioeconomic burden of CNS damage, which is on the rise globally. The spiny mouse (Acomys) has the unique ability amongst mammals to regenerate its CNS scar-free. How regeneration unfolds from the Acomys genome remains unknown. Here, we propose to identify the genetic basis of scar-free regeneration in Acomys through comparative multiomic analysis against mouse, the best characterized non-regenerative model. We will first apply cutting-edge single-cell and spatial gene expression and chromatin accessibility profiling to map gene regulatory programs within the injured spinal cord of both species. We will then use machine learning to identify key pro-regenerative pathways specifically activated in Acomys. Finally, we will functionally validate these pro-regenerative candidates using therapeutically-relevant gene therapy vectors in preclinical models of spinal cord injury. Together, by deciphering the "regenerative code" in the Acomys regulatory genome, we aim to unlock novel therapeutic targets for gene therapies promoting scar-free repair and functional recovery after CNS damage. We expect that this project and its long-term development will advance regenerative medicine in the CNS while establishing Acomys as a central model organism.
Popular science description
Some animals, like fish and salamanders, have a remarkable superpower—they can grow back lost body parts, including their central nervous system. Unfortunately, mammals, like us humans, can't do this. When we get injuries to our central nervous system, our bodies just create a scar, which doesn't fix the lost functions and can lead to lasting disabilities. Scientists have been studying these regenerating animals to figure out the secrets of their healing abilities. They've found that these creatures use special stem cells and kickstart genes that are usually active only when they're developing before birth. But it's tough to take what we learn from these animals and use it to help humans because we're just too different. Enter the African spiny mouse, a unique little mammal that can also regenerate like these other amazing creatures. It doesn't just heal wounds; it can fix its spinal cord without any scarring! This makes the spiny mouse super interesting for scientists because it's closer to us genetically. Researchers from Sweden and Korea are teaming up to study the spiny mouse and compare it to regular mice, which can't regenerate. They've got some high-tech tools and know-how to map out every detail of what happens at the gene level during healing. The plan is to create a complete picture of the healing process by looking at individual cells and where they're located. They're hoping to find the genes that help the spiny mouse heal without scars. Then they'll test ways to turn on these healing genes in injuries. This could lead to new treatments that help people heal better after spinal cord injuries or other central nervous system damage. If they crack the code of the spiny mouse's healing powers, we might one day be able to repair our bodies just like they do—a big win for medicine!