Enhancing axonal regeneration in the spinal cord through inhibition of TGFβ signaling
Funded in: 2014, 2015, 2016
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Problem: Myelin and chondroitin sulphate proteoglycans (CSPGs) inhibit axonal growth.
Target: Transforming growth factor β (TGFβ) receptor might be able to inhibit both.
Goal: TGFβ receptor as a new target for drug design, leading to the development of new treatments for clinical use.
Introduction: For many years it was believed that the spinal cord was incapable of regenerating after injury, but it is now known that the spinal cord contains several molecules that inhibit the growth of axons, the long nerve fibers that carry information from the brain. Two of the most important inhibitory molecules are myelin, the waxy substance that surrounds axons, and chondroitin sulphate proteoglycans (CSPGs), which are produced by cells called astrocytes. Studies have shown that blocking the function of these molecules can improve regeneration.
Problem: Researchers have used many different methods to reverse the effects of myelin and CSPGs, but most of these studies have focused on only one of these molecules. This project will determine if targeting a receptor called the transforming growth factor β (TGFβ) receptor can reduce inhibition by both myelin and CSPGs, and thereby produce more extensive regeneration.
Methods: Two different drugs that inhibit the TGFβ receptor – SB431542 and SB505124 – will be used in the experiments. First it will be tested whether these drugs can promote axon growth when neurons are grown in myelin-coated dishes. Then the team will use models of optic nerve and spinal cord injury to determine if treatment with SB431542 and SB505124 improves axonal regeneration.
Expected Results: Based on preliminary findings, it is anticipated that administration of SB431542 and SB505124 will enhance axonal regeneration in the presence of myelin, and reduce levels of CSPGs within the injured spinal cord.
Potential application: If these experiments are successful, they will establish the TGFβ receptor as a new target for drug design, and this could lead to the development of new treatments for clinical use.