Timothy Vartanian, M.D., Ph.D.
Professor of Neuroscience
To prevent injury to and promote regeneration of myelin in people with MS. Multiple sclerosis – scarring of the brain – begins with injury to oligodendrocytes, the myelin forming cells of the Central Nervous System. Eventually, the body’s natural capacity for remyelination is foiled altogether. This destructive process has defied scientific understanding for over 150 years. Key points of study include:
- Myelin Regeneration
- Environmental triggers of MS
- Clostridium perfringens epsilon toxin
- Mechanisms of demyelination in MS
- Pattern recognition receptors functioning in the inhibition of myelin and axonal regeneration
- Oligodendrocyte cell death in MS
Link to Multiple Sclerosis Center Website:
Yinghua Ma, Ph.D.
Rashid Rumah, M.D., Ph.D. Candidate
Jennifer Linden, Ph.D.
Myat Lin Oo, Ph.D.
One of the vital questions we need to solve to help people with MS is the problem of myelin regeneration. At Weill Cornell, we theorize that some individuals normally remyelinate robustly and others do not. Over time, the normal myelin regenerative capacity diminishes. The goal is to develop drugs that can promote myelin regeneration. The hurdles that require intensive research are how to measure myelin regeneration in a living human being, and identifying molecular targets that will enhance myelin regeneration.
Why is this important?
Myelin is an insulating substance made by a cell in the nervous system called the oligodendrocyte. Myelinated axons conduct information at tremendous velocities approaching 150 meters per second (that's about 335 miles per hour). By contrast, unmyelinated axons conduct information at velocities of 1/2 to 10 meters per second (that's 22 miles per hour at best). By analogy your brain prefers to drive a Ferrari, and regions that are demyelinated are forced to ride a bicycle. When you consider the trillions of connections in the brain, you can begin to understand why there is a need for speed.
As important as speed of conduction, myelin also is essential to axonal and neuronal health. Without myelin, axons and nerve cells degenerate. Keeping your nervous system healthy means keeping myelin healthy. This is why we devote so much of our effort to this problem of myelin regeneration.
What are we doing at WCMC to solve this problem?
Developing drugs that promote myelin regeneration
During an MS attack, the myelin forming cells of the central nervous system (oligodendrocytes) are killed. Normal remyelination requires stem cells within the brain to differentiate into oligodendrocytes and then form myelin. The brain has abundant stem cells that can become oligodendrocytes termed oligodendrocyte progenitor cells (OPCs). Unfortunately, injury to the brain tissue during an MS attack results in the liberation of molecules that prevent the OPCs from becoming myelin forming oligodendrocytes and remyelination fails. We have identified the molecular pathway that prevents this normal myelin regeneration in Multiple Sclerosis. We have developed a method to screen for drugs that target this pathway that we will validate in models of remyelination and then proceed to clinical trials.
- Identification of low molecular weight hyaluronan as an inhibitor of myelin regeneration.
- Identification of the TLR2/MyD88 pathway as a signaling pathway mediating hyaluronan and other extracellular matrix molecule mediated inhibition of remyelination in multiple sclerosis.
- Identification of toll-like receptor signaling in neurons as inhibitors of axonal regeneration.
- Identification of MyD88 as a regulator of neuronal homeostasis.
- Identification of C. perfringens epsilon toxin as a trigger for multiple sclerosis and nascent lesion formation.
1: Rumah KR, Linden J, Fischetti VA, Vartanian T. Isolation of Clostridium perfringens Type B in an Individual at First Clinical Presentation of Multiple Sclerosis Provides Clues for Environmental Triggers of the Disease. PLoS ONE. 2013
2: Nguyen TD, Wisnieff C, Cooper MA, Kumar D, Raj A, Spincemaille P, Wang Y, Vartanian T, Gauthier SA. T2 prep three-dimensional spiral imaging with efficient whole brain coverage for myelin water quantification at 1.5 tesla. Magn Reson Med. 2012 Mar;67(3):614-21. doi: 10.1002/mrm.24128. Epub 2012 Jan 3. PubMed PMID: 22344579.
3: Li J, Gu X, Ma Y, Calicchio ML, Kong D, Teng YD, Yu L, Crain AM, Vartanian TK, Pasqualini R, Arap W, Libermann TA, Snyder EY, Sidman RL. Nna1 mediates Purkinje cell dendritic development via lysyl oxidase propeptide and NF-κB signaling. Neuron. 2010 Oct 6;68(1):45-60. doi: 10.1016/j.neuron.2010.08.013. PubMed PMID:20920790.
4: Rocuts F, Ma Y, Zhang X, Gao W, Yue Y, Vartanian T, Wang H. Carbon monoxide suppresses membrane expression of TLR4 via myeloid differentiation factor-2 in betaTC3 cells. J Immunol. 2010 Aug 15;185(4):2134-9. doi: 10.4049/jimmunol.0902782. Epub 2010 Jul 14. PubMed PMID: 20631306.
5: Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11555-60. doi: 10.1073/pnas.1006496107. Epub 2010 Jun 3. PubMed PMID: 20534434; PubMed Central PMCID: PMC2895128.