Understanding the molecular basis of myelination, and the nature of the cells that achieve myelination, is of fundamental importance for both basic and clinical neuroscience. Detailed insights into these processes are likely to provide the foundation for therapeutic approaches to diseases affecting myelinating cells, like Multiple sclerosis in the central nervous system (CNS) and Peripheral Neuropathies in the peripheral nervous system (PNS). The host lab has shown that integrin-mediated signals derived from the extracellular matrix together with growth factor signaling via tyrosine kinase receptors are critical for the correct development of myelinating cells and their interaction with neurons. Particularly critical signals integrators are ILK (integrin-linked kinase), as well as the small RhoGTPases Rac1 and Cdc42. Complementary lines of research point to a connected critical role of the PI3K/Akt pathway. The two mTOR-containing complexes 1 (mTORC1) and 2 (mTORC2) are major regulators of these signaling pathways. In this project, we will examine the functional role of mTORC1 and mTORC2 in the development of myelinating cells and during remyelination after injury. To achieve these goals we will use conditional floxed alleles in the mouse that target two critical subunits of the mTOR complexes, raptor (mTORC1) and rictor (mTORC2). These mice are already available in the host laboratory. Using well established Cre recombinase expressing mouse strains, we will eliminate rictor and raptor individually and in combination specifically in developing Schwann cells in the PNS, as well as in mature Schwann cells followed by peripheral nerve injury. If time allows, we will perform complementary experiments in the CNS, using oligodendrocyte-specific gene knock out mice. The work will be embedded in ongoing work in the host laboratory examining the functional role of mTORC1 and mTORC2 in neural stem cell lineage decisions.
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