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Defining macrophage-nerve dependent signals in the regulation of limb regeneration

Project Summary

The regeneration and scar-free healing of various body parts and tissues in salamanders provide natural examples of repair processes, that if understood, have the capacity to improve human health in an almost unlimited range of applications. Significant progress has been made in the last 2 decades in identifying key steps along with the cells and molecules that facilitate these advanced healing and repair pathways. The candidate’s previous research identified the Anterior Gradient Protein (AGP) Family of proteins in regeneration that underpin the molecular basis of nerve dependence. Additional research identified the requirement for innate immune cells such as macrophages in a successful regeneration program. These two requirements for regeneration are linked by the AGP induction in nerve Schwann cells in response to the inflammatory signals provided by macrophages. This project will extend on this work by mapping the temporal expression pattern of distinct AGP family members during limb regeneration and identify the spatial/temporal association with innate immune cells using a range of complementary techniques. Common and distinct AGP molecular targets will be identified using AGP overexpression with downstream high throughput gene expression and proteomic analysis. Although one specific AGP family member can successfully substitute for nerve, other family members have not been tested. This project will evaluate the potential for part or full rescue of regeneration with alternative AGP family members. Macrophage-specific signals that regulate the nerve dependent phase of regeneration will be identified using both the Accessory Limb Model of ectopic limb induction and with cells purified from regenerative tissue via flow cytometry. Candidate molecules will be evaluated in regeneration induction assays to substitute for macrophages/nerve in regeneration. This project will provide information critical for understanding the neuro-immunological axis in regeneration and help identify the molecular signals that guide the regeneration process. This work will lay the foundation for identifying the signals from nerves and macrophages that can be exploited in promoting novel repair in human tissues.

Relevance of Research

The lack of efficient repair in human tissues damaged by traumatic injury, disease or surgery causes significant morbidity and mortality in humans. Understanding how salamanders faithfully repair or replace whole structures such as the limb or sections of the heart, brain or spinal cord, would dramatically improve human health. Salamander scar free-healing and regeneration serves as a template for improving human repair along with the identification of gene networks shared with humans and novel cross-reactive molecules.