The overall goal of this proposal is provide critical research and career training for the PI as he transitions to becoming an independent physician scientist in the field of neurodevelopment and myelination. The scientific objectives are to determine the contributions of mTOR kinase signaling in oligodendrocytes to myelin formation and the consequences of mTOR dysregulation. The objectives of this work stem from our own studies of mTOR deregulation in animal models as well as from patient derived imaging data suggesting abnormalities in myelination in Tuberous Sclerosis Complex (TSC). We will test the hypothesis that white matter pathology in TSC is due to alterations in mTORC1 and mTORC2 signaling in oligodendrocytes. As the vast majority of patients with TSC have epilepsy and approximately 50% of patients have autism spectrum disorder, the proposed studies have additional significance for the related fields of epilepsy and autism. In addition, basic science studies of oligodendrocyte function and their relationship to white matter integrity are receiving much more attention and should be a fruitful field for me to build an independent research career. Our proposed studies will focus on how mTORC1 and mTORC2 activity contribute to oligodendrocyte function and myelination. As both increased mTORC1 and decreased mTORC2 activity are seen in TSC, we will utilize a genetic approach to independently target the Tsc2 gene, resulting in increased mTORC1 activity and decreased mTORC2 activity, and the Rictor gene, resulting in just decreased mTORC2 activity in mouse oligodendrocytes. We will subsequently define the structural and functional consequences of altered mTOR activity in oligodendrocytes. Finally, we will define how loss of the Tsc2 and Rictor genes contributes to behavior and epilepsy and define whether alterations in the mTOR signaling pathway may contribute to autism relevant behaviors in a mouse model. I am well positioned to achieve the aims of this research project. I have past experience in generating and characterizing animal models of TSC and we possess the tools and reagents required to complete all of our stated aims. The proposed work will also allow me to form collaborations to expand my breadth of experimental tools to include neurophysiology, electron microscopy, and animal behavioral analysis. This proposal supports my immediate goals of defining the contribution of mTOR signaling to myelination, expanding my repertoire of experimental techniques, and supporting my transition to independence. Importantly, the study of myelination in developmental disorders is a relatively underrepresented field of research despite its translational significance. While outside the breadth of this proposal, future studies may have relevance to periventricular leukomalacia, a common cause of cerebral palsy in premature infants, schizophrenia and cryptogenic autism. With the support of a K08 award, I can achieve my long-term goal of becoming an independent investigator in the fields of neurodevelopment and myelination.
The primary goal of this proposal is to determine how genes which are altered in the human disease Tuberous Sclerosis Complex contribute to brain myelination. An additional goal is to further train and develop a physician scientist to provide th skills required to make a contribution in the field of human neurodevelopment.