Interleukin-1α inhibition as a potential neuroprotective therapy for spinal cord injury
Funded in: 2018, 2019
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Problem: The inflammatory response after SCI contribute to secondary damage in the spinal cord
Target: molecular factors involved the inflammatory response
Goal: promote spinal cord repair after injury by blocking specific factors
Over four million individuals are afflicted by different types of spinal cord injury (SCI). One of the consequences of SCI is the loss of neural tissue at the site of injury. This results in an inflammatory response characterized by the entry of immune cells that are essential for the clearance of cellular debris. It has been assumed that during this process the inflammatory response may also contribute to secondary bystander damage in the spinal cord, causing the death of neighboring neurons and myelin-producing cells called oligodendrocytes. As a consequence of this, both lesion volume and demyelination increase with time. Because of the inability of the human spinal cord to repair itself, damages sustained after injury often lead to permanent functional deficits for which no cure is currently available. Among the factors that mediate the inflammatory response are molecules normally found within cells that get released upon cell lysis. These intracellular host molecules, called danger signals, include the inflammatory protein interleukin-1 alpha (IL-1α). IL-1α is normally sequestrated inside the nucleus of cells, where it regulates the expression of genes. However, when released after cell damage and death, it becomes a powerful activator of inflammation. We recently discovered that in addition to its role in inflammation, IL-1α can act on oligodendrocytes to reduce their expression of genes coding for cell survival. The main goal of this research proposal is to identify the cellular and molecular mechanisms involved in this response and to utilize this knowledge to promote spinal cord repair after injury. Blocking IL-1α or its downstream target gene products may prevent secondary bystander damage and spinal cord demyelination, and thus could have implications for traumatic spinal cord and brain injury as well a central nervous system demyelinating diseases.