Collaborative MS Research Center Award
Wendy Macklin, PhD
University of Colorado School of Medicine, Denver, CO
Bruce Appel, PhD
Jeffrey Bennett, MD, PhD
Michael Graner, PhD
V. Michael Holers, MD
Gregory Owens, PhD
Kenneth Tyler, MD
Exploring brain cell interactions to shed new light on how damage occurs in MS and how to reverse the process to restore function to people with MS.
MS involves immune system attacks on the brain and spinal cord. Glial cells are essential cells in the brain and spinal cord, and they interact among themselves and with nerve cells. One glial cell type is the oligodendrocyte, which generates the myelin that supports and insulates nerve fibers, and which can be damaged in MS. This cell interacts both with nerve cells and with other glia, such as astrocytes. Damage to astrocytes can lead to damage to both oligodendrocytes and myelin. The Collaborative MS Research Center team is focusing on developing a new series of collaborations to investigate how interaction among glia and other brain cells impact myelin damage, and on developing therapeutic approaches to counteract the damage and restore function to people with MS.
To understand critical interactions between glial cells that mediate damage in MS, we need to understand the types of normal interactions that occur. This is a relatively understudied area. Dr. Macklin has investigated oligodendrocyte development for many years. Her team is focusing on how glial cells communicate with each other in vivo, and also studying this in isolated astrocytes, oligodendrocytes, and other glial cells in culture. Dr. Tyler is a neurovirologist with extensive experience in developing and using culture systems to study viral pathology in these cells and in neurons to understand viral-mediated damage to the brain.
One exciting aspect of this Center is an investigation of the use of “exosomes,” small vesicles that can be released from cells and taken up by other cells. Dr. Graner has pioneered the study of exosomes for their potential as drug delivery systems for treating brain tumors. He is providing expertise and resources to determine whether glial cell-cell communication can be mediated by this novel cell signaling system. The team is treating glial cells with exosomes from other glial cells to assess the impact on cell survival, proliferation and differentiation.
The zebrafish model has remarkable potential as a tool for understanding these interactions. Brain development in these small, fresh water fish occurs within days, and since the embryos are translucent, it is easy to observe myelin formation and other processes in the living fish. Furthermore, generating mutations in these fish is a well-established process. Dr. Appel has used zebrafish to screen for mutations that impact oligodendrocyte development and myelin formation, and can do live imaging of the interactions of glial cells to provide new insight into their impact on myelination.
The team also is studying the impact of immune antibodies in MS. Dr. Owens, in collaboration with Dr. Bennett, has developed unique tools to characterize these immune system proteins. They are tracking common or distinct pathways through which disease-specific MS antibodies cause injury to myelin and nerve cells. They have cloned over 130 different antibodies from people with MS and other neurological disorders for use in this project. The goal is to understand whether any of these MS antibodies impact the glial network, either by directly or indirectly inducing cell dysfunction. Dr. Holers is lending expertise in “complement,” another aspect of immune defenses, to investigate its potential role in glial and nerve cell injury.
Center investigators and their laboratories are meeting monthly, with members presenting relevant published journal articles or research-in-progress. The team also is bringing in two outside MS researchers each year to present at these seminars and to meet with members of the Center.
This talented group is tackling an understudied area of MS research that promises to shed new light on why damage occurs and how to restore function to the nervous system.