Multiple Sclerosis

A key determinant of progression of most neurodegenerative diseases including MS is age. Studies have reported the deficient clearance of myelin debris, and increased formation and deposition of cholesterol crystals within macrophages, in the aging CNS after demyelination. This has been associated with reduced expression of cholesterol exporter ABCA1 with age. As myelin contains about 80% of lipids, we propose that the accumulation, deficient processing and shuttling of lipids or lipid droplets contribute to the impaired myelin debris clearance in an injured aging CNS. We aim to address the deficient phagocytosis by macrophage and microglia using CX3CR1 promoter-driven Ai9 mice. In culture we aim to test the handling of myelin-associated lipids on murine and human macrophage/microglia, and then target therapeutically the processing of intracellular lipid. Debris impedes the repair process in the lesion, so this work will help us to achieve bioenergetically conducive environment for the repair. 

Researcher: Manoj Mishra 

I am researching the mechanisms of leukocyte trafficking into the brain during multiple sclerosis (MS) pathogenesis. Using the Experimental Autoimmune Encephalomyelitis (EAE) mouse model for MS, I am working on a project pertaining to understanding the metabolic requirements and its underlying mechanisms within myeloid cells in EAE/MS. In this regard, I am investigating the role of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) in governing enhanced glycolysis in pro-inflammatory myeloid cells. Using genetic tools to conditionally ablate EMMPRIN from CCR2+ monocytes (CCR2Cre^tm:EMMPRIN^fl/fl mice), I am currently studying its involvement in mediating EAE/MS pathology. In addition to my interests in monocyte/macrophages, I am also looking into the pathogenic role of pericytes and astrocytes.

Researcher: Deepak Kaushik

Remyelination in multiple sclerosis (MS) can restore physical function and exert a neuroprotective role. Due to various causes, remyelination becomes gradually insufficient in most patients. Since chondroitin sulfate proteoglycans (CSPGs) deposited into the lesion microenvironment inhibit remyelination, blocking their synthesis after demyelination could improve tissue repair. Using a recently described transgenic mouse line, we will be able to label and follow the fate of newly formed oligodendrocytes in lesions and monitor remyelination in experimental autoimmune encephalomyelitis (EAE), which recapitulates many features of MS pathogenesis. We will unravel the role of CSPG on remyelination through promoting Th17 responses and determine the effect of inhibiting CSPG synthesis on repair in EAE, thereby proposing a novel therapy for MS. We hope to develop a CNS-targeted therapy to reduce the side effects of CSPG synthesis blocker.

Researcher: Samira Ghorbanigazar

B cells can promote and suppress the progression of MS but we currently do not know which subsets of B cells exist in the brain, their locations in the brain, or the mechanisms that B cells are using to modulate MS progression. In my project, I will address these problems by fully characterizing the locations and subsets of B cells in MS lesions. Using an animal model and cells in culture, I will identify the major mechanism(s) that B cells are using to promote or suppress CNS damage and determine whether cellular interactions in MS lesions influence B cell pathogenesis.

Researcher: Rajiv Jain

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Parenchymal demyelination begins perivascularly and continues outward from there. Pericytes are cells that sit at the junction of the blood-brain barrier and have important roles in regulating this barrier, including immune cell trafficking. In pericyte depletion studies, it has been shown that pericyte loss can lead to neurodegeneration and white matter dysfunction. In my project, I am aiming to characterize the pericyte response following demyelination using the lysolecithin model, understanding the mechanisms of interaction between pericytes and cells such as Oligodendrocyte progenitor cells that are critical for regeneration, and to study how this is affected by both aging and exercise. Pericytes occupy a critical niche at the border of the blood-brain barrier that allows them to control and mediate neuroinflammation. Despite their position in the neurovascular niche, they remain understudied, but an intriguing therapeutic target.  

Researcher: Brian Lozinski

Current treatments for MS focus on relapse-remitting MS, in contrast to primary progressive MS (PPMS), which skips the relapse-remitting phase and disease immediately begins to progress. With a lack of current treatment options for PPMS, my research seeks to unveil an effective and affordable treatment for the PPMS population. We will investigate two inexpensive generic drugs: Indapamide, a high blood pressure medication and antioxidant, and Hydroxychloroquine (HCQ), an anti-malarial drug known to inhibit microglia, an immune cell of which increased activation is a hallmark of PPMS. Over-activation of microglia results in the degradation of myelin, an insulator surrounding nerve cells, along with myelin-producing cells. This breakdown releases molecules contributing to free radical formation, thus enhancing the risk of disease progression. Using in vitro models along with the lysolecithin mouse model of MS, we will observe the effects that the combination of these drugs has on neuron and oligodendrocyte protection, demyelination, and inflammation. With HCQ currently in a Phase 2 clinical trial for PPMS and indapamide demonstrating promising effects on free radicals in animals, there is optimism that in combination the drugs will have strong therapeutic potential, giving rise to a new treatment plan to fill the void that currently exists for PPMS.

Researcher: Dennis Brown

Following myelin destruction, the brain has an innate repair system in which immature cells called oligodendrocyte precursor cells (OPCs) migrate to the lesion, develop into mature cells, and replace the damaged myelin. There is an inhibitory environment in the MS lesion that prevents OPCs from entering and maturing into myelin-forming cells. The aim of my research is to overcome this inhibitory environment with a focus on chondroitin sulphate proteoglycans (CSPGs). I am studying a particular CSPG member in the CNS called versican V1. Versican V1 is of interest because while high during CNS development, it is not seen in the adult CNS until injury. My work involves tissue culture work and experiments with a transgenic mouse line. My hypothesis is that CSPGs, particularly versican V1, physically restrain process elongation, proliferation, migration and maturation of plated OPCs, and that the conditional removal of versican V1 in lesions will lead to enhanced OPC numbers and remyelination. There are no current therapeutic approaches to induce remyelination in MS and this study hopes to shed light on the most important inhibitor of OPCs and propose a specific targeting strategy that is permissive of remyelination.

Researcher: Emily Jelinek