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Research Highlight

A major focus of ongoing research at UC Irvine is to develop new therapeutic strategies designed to limit ongoing demyelination while repairing damaged nerve tissue.

Dr. Mike Demetriou, M.D., Ph.D.

Dr. Demetriou is one of the first graduates from the University of Toronto’s prestigious MD/PhD program, a dual degree program providing both medical and research training. After completing the PhD component of the program, where he focused on genetics and cancer research, Mike became interested in neurology during his senior years of medical school. He launched into the field of Neurology by applying his prior research experience to well-known neurological diseases. He observed that his prior research might be applicable to auto-immune diseases – like Multiple Sclerosis (MS) – which led to a year of postdoctoral research on mouse models of MS. From that point on, he has focused his clinical and research efforts in MS, applying his talents to making contributions towards a cure for MS.

In 2001, Dr. Demetriou published a paper in the prestigious journal NATURE, revealing that auto-immune disease was triggered in mice following the disruption of protein glycosylation (i.e. the addition of sugars to proteins). However, it was the proposed mechanism that was quite novel – sugars binding to proteins to create a lattice-like network on the surface of cells, with this lattice network controlling the concentration and level of receptors on the cell surface. Mike found that disrupting the addition of sugars to proteins weakens the lattice, inducing T-cell hyper-activity thereby resulting in an unfavorable auto-immune response.

Following these findings, Mike came to the University of California, Irvine, where he continued to expand on the idea of how this lattice network regulates T-cells and autoimmunity. Using in-bred strains of mice that differ in their genetics, Mike demonstrated that the strength of the lattice and associated susceptibility to autoimmunity was regulated by both genetic inheritance and cellular metabolism. Depending on the in-bred mouse strain examined, defects in the lattice were associated with kidney auto-immune disease or a spontaneous MS-like disease.

Next, Mike and his team wished to examine whether protein glycosylation and the lattice are similarly altered in humans with MS. It has long been known that environmental and genetic factors combine to induce MS, however how they do this at a molecular level is largely unknown. Mike and his team revealed that multiple human genetic factors and multiple environmental factors converge to alter protein glycosylation and the lattice, thereby controlling T-cell activity and MS risk. Environmental regulation by Vitamin D3 and cellular metabolism converge with genetic risk factors in cytokine receptors for IL-2 and IL-7, CTLA-4 and Mgat1 to weaken the lattice and induce T-cell hyper-activity.

Vitamin D3 is synthesized in the skin following UV light exposure from the sun. Vitamin D3 deficiency has long been associated with MS, whereas higher levels of vitamin D3 have been shown to inhibit mouse models of MS. Mike and his team revealed that Vitamin D3 enhances protein glycosylation and the lattice to suppress T-cell hyper-activity associated with MS and inhibit mouse MS models.

A major unmet need for the management of MS is an inexpensive oral therapy that directly targets an underlying disease mechanism, rather than non-specific immunosuppression. Indeed, Mike’s most recent work has revealed that the simple sugar and dietary supplement N-acetylglucosamine (GlcNAc), which is similar to the more widely available glucosamine, rescues defective protein glycosylation in MS cells in culture and inhibits pro-autoimmune T-cell responses and mouse models of multiple sclerosis and autoimmune diabetes when given orally. This suggests that oral GlcNAc may provide a simple and inexpensive therapeutic strategy to target an underlying defect in protein glycosylation that induces pro-autoimmune immune responses in MS and potentially other human autoimmune diseases. Mike is currently planning a human clinical trial to further investigate this possibility.

When asked what he’ll do when he finds a cure for MS, Dr. Demetriou replies, “That is a tall order, but if I were so lucky, I would move on to examine other auto-immune disease, like Crones disease or type I diabetes.” We like what we hear!

As an MD, Mike regularly sees MS patients at the National Multiple Sclerosis Society designated Comprehensive Care clinic at Gottshalk Medical Plaza on the UC Irvine campus. The clinical center is distinguished for being currently only one of three such centers in California.

When he’s not exploring and discovering in the lab or seeing patients, Mike enjoys spending time with his family and outdoor adventures, especially around his hometown of Toronto, Canada.

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