Molecular Mechanisms and Therapeutic Potential of Heparan Sulfate Proteoglycans in Remyelination
Abstract
The Focus Area of this application is Central Nervous System Regenerative Potential in Demyelinating Conditions. The application utilizes a series of mechanistic studies to investigate the mechanisms by which the hostile inhibitory signaling environment in MS is generated and presents obstacles to repair in Multiple Sclerosis (MS). The hypothesis that heparan sulfate proteoglycans (HSPGs) are involved in these processes is novel and our approach is highly innovative as it utilizes a comprehensive set of new transgenic mice in carefully selected animal models. The brain contains a population of progenitor cells, commonly referred to as oligodendrocyte progenitor cells (OPCs), that can give rise to specialized cells known as oligodendrocytes. Oligodendrocytes and the myelin that they produce are vital for normal neurological function. When oligodendrocytes are lost or damaged in demyelinating diseases such as MS this contributes to severe and progressive disability. Importantly, OPCs can generate new oligodendrocytes, restoring lost myelin and promoting functional regeneration known as remyelination. As such, OPCs represent a promising untapped source of stem/progenitors that when properly stimulated could lead to significant regeneration in MS and other diseases. In MS, remyelination is thought to occur slowly over several months and is often insufficient. As a result, regions of permanent or chronic demyelination are commonly observed in patients with MS. As chronic demyelination is associated with neuronal death and the loss of neurological function, therapies aimed at enhancing remyelination are expected to restore lost function and prevent disease progression in MS. We have begun deciphering a series of new mechanisms by which a class of proteins decorated with sulfated sugar sidechains known as heparan sulfate proteoglycans (HSPGs) can be modulated to improve remyelination. We recently identified sulfatase enzymes as part of a new mechanism that limits remyelination in animal models. Our initial studies found that genetic and pharmacological inhibition of sulfatases could accelerate remyelination in an animal model of toxin-induced demyelination. These enzymes play a relatively small part in a complex network of proteins along with enzymes that synthesize and modulate their heparan sulfate sugar sidechains. This network is collectively known as the heparanome and represents a new area for remyelination research. Unlike previous approaches that have typically focused on a single receptor-mediated pathway, the heparanome interacts with several pathways in a highly coordinated manner. As such, we anticipate that modulation of this novel component of the lesion environment will be fruitful in our search for effective strategies to improve remyelination. In the current proposal, we are working to define the precise make-up of inhibitory HSPGs, to define the potential contribution of HSPG inhibition in regions of grey matter injury, and ask whether small molecules can result in therapeutic improvement in the mouse EAE model of MS. The results from these studies will provide critical information on the HSPG-dependent cell-cell interactions that act during demyelination and further the identification of factors that promote myelin repair in MS. Our goals are to (1) determine the specific contributions of synthetic enzymes known as 2-S and 6-S sulfotransferases on HSPG signaling following demyelination, (2) determine the role of neuron-expressed sulfatase, an enzyme capable of editing HSPG sulfation, and ask if this mechanism contributes to the inhibitory environment present in cortical lesions in the MS brain, and (3) determine the therapeutic potential of heparan sulfate mimetics as agents to promote remyelination in EAE. The animal models we will employ provide insight into specific aspects of the regenerative process in MS and allow us to determine the potential for these strategies when translate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310682
Entities
People
- Fraser J Sim
Organizations
- United States Army
- University at Buffalo