Demyelinating diseases such as multiple sclerosis (MS) are characterized by the loss of myelin in the central nervous system (CNS). While remyelination by oligodendrocytes (OLs) occurs in earlier stages of MS, it results in considerably thinner myelin sheaths than those produced during development. Additionally, myelin repair eventually fails in MS, leading to progressive disabilities in afflicted patients. It is thought that decreased OL differentiation, maturation, and subsequent myelination in these conditions are limiting factors in functional recovery. Therefore, understanding the signaling pathways regulating differentiation and maturation of oligodendrocyte progenitor cells (OPCs) and the production of myelin will be crucial in developing techniques to promote remyelination. Previous research has shown that the PI3K/Akt/mTOR intracellular signaling pathway is critical in these processes. Inhibition of this pathway leads to sustained hypomyelination in the spinal cord and delayed hypomyelination in the brain. Based on published and new preliminary data, I hypothesize that mTOR signaling regulates de- and remyelination of the brain through promoting OL survival, production, and myelin integrity, making downstream effectors promising targets for promoting myelin repair. To address this hypothesis, I will determine how 1) loss of mTOR affects susceptibility to demyelination of the brain, and 2) loss of mTOR affects efficiency of remyelination in the brain. Successful completion of the experiments proposed in this grant will reveal if mTOR signaling limits demyelination or is necessary for myelin production and repair, and aid in determining whether this pathway represents a potential target for promoting myelin repair.
Multiple sclerosis, a demyelinating disease of the CNS, affects over 2 million people worldwide, decreasing patient quality of life through the progressive accumulation of disabilities. As previous studies have highlighted the importance of the mTOR signaling pathway in developmental myelination and myelin maintenance, I will investigate the effect of mTOR signaling on myelin repair of the brain. Results from the experiments proposed in this grant will provide key insight on the regulation of oligodendrocyte development and myelin plasticity in the demyelinated CNS, and the potential of the mTOR signaling pathway and downstream effectors as therapeutic targets.
