Defining and Overcoming a Novel Extracellular Matrix Inhibitor of Remyelination in MS: Fibulin-2
Abstract
FY21 MSRP IIRA Focus Area: Central nervous system regenerative potential in demyelinating conditions, and specifically Obstacles to repair and approaches to overcome and achieve remyelination In Multiple Sclerosis (MS), oligodendrocytes and the myelin that they make and maintain are lost in the brain and spinal cord. There are spontaneous attempts at repair within lesions, and these take the form of the generation of new oligodendrocytes from oligodendrocyte precursor cells (OPCs). The new oligodendrocytes then extend and reform myelin on nerve fibres that have lost their myelin sheath. This process is called remyelination. There are many advantages to remyelination, including the restoration of conduction of signals along nerve fibres, and the protection by the newly formed myelin of the denuded nerve fibres from further deterioration. Best yet, there might be restoration of lost deficits with remyelination, as has been demonstrated in experimental animals where, for example, cats with loss of vision regain sight upon remyelination of the optic nerve. Thus, with spontaneous attempts at repair that occur naturally in MS, and the benefits of remyelination, there are active research efforts ongoing worldwide to seek to enhance remyelination in people living with MS. The repair of myelin would benefit all stages of MS, including progressive MS to slow progression of disability, or to elicit some return of function. Research at promoting remyelination in people with MS has met with the realization that there are many inhibitors to the repair process within MS lesions. In particular, the lesion is very hostile by containing a number of obstacles to repair, including the aberrant expression of proteins that are called extracellular matrix molecules. We have described one such class of extracellular matrix molecules, the chondroitin sulfate proteoglycans (CSPGs), as inhibitory to myelin repair, and we have been seeking approaches to neutralize CSPGs to promote remyelination. During the course of this research, we have asked if there are other equally (or perhaps even more) relevant extracellular matrix molecules expressed in MS lesions that might also be critical obstacles to the repair process. By mining public databases, we have discovered that an extracellular matrix molecule, Fibulin-2, is highly expressed in lesions of MS as well as its animal models. There is so far no association of Fibulin-2 with MS outcomes at this point in the literature. Thus, we have gone forth and sought data to determine whether Fibulin-2 is an inhibitor to myelin repair process. Our preliminary results indicate that this is indeed the case. In this proposal, we seek to establish the concept that Fibulin-2 is contained within most MS lesions that do not repair, and we seek to understand how Fibulin-2 inhibits the myelin repair process. This approach will help us to develop new drugs to overcome Fibulin-2. Moreover, we will combine overcoming both Fibuln-2 and the CSPGs to determine whether inhibiting both obstacles would provide a better efficacy of myelin repair in lesions of animal models of MS. We are introducing new strategies, particularly drugs that are targeted to lesions within the brain and spinal cord to overcome CSPGs, and we hope to do the same to overcome Fibulin-2. In general, these experiments are aimed at establishing the critical importance of Fibulin-2 and also CSPGs, in lesions of MS where they impede the repair process. Besides creating fundamental new knowledge, the experiments will also test new therapeutics in experimental animals so that the repair of lesions occurring in MS can be substantially enhanced in the future. The ultimate goal is to provide a milieu within MS lesions that is very conducive for repair, so that meaningful functional recovery in all forms of MS can be ultimately achieved.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210468
Entities
People
- V. Wee Yong
Organizations
- United States Army
- University of Calgary