Myelin is a crucial component of our nervous system. In the CNS, specialized cells known as oligodendrocytes (OLs) differentiate from precursor cells (OPCs) and produce myelin by wrapping their plasma membranes around axons. Myelin's main function is to insulate axons and allow for the fast conduction of electrical impulses, and myelin damage as seen in preterm white matter injury and multiple sclerosis can lead to permanent neurological disability. Currently no therapy exists for repairing this damage, but promoting OL differentiation and myelination is a promising strategy. It is therefore important to understand how these processes are regulated. My long term research goal is to understand the microenvironmental factors that regulate OL differentiation and myelination. My short term goals are to (1) uncouple OL differentiation and myelination and determine whether dynamic neuronal signaling has a role in regulating either process, and (2) support a role for astrocytes in regulating OL differentiation. I will pursue my first aim in the lab of Dr. Jonah Chan, an expert in neuronal-glial interactions, during phase I of the K22 award. To examine the role of dynamic neuronal signaling I propose to completely eliminate it along the optic nerve by enucleating one eye of Wlds mice. I will do this at two time points, an early time point to analyze OL differentiation and a later time point to analyze myelination. I will also determine whether axon diameter is the main determinant of myelination by performing enucleations in transgenic mice whose optic nerve axons are larger than normal (Pten cKOs). My preliminary findings indicate that (1) OL differentiation and myelination are regulated by distinct mechanisms and (2) dynamic neuronal signaling is not required for OL differentiation. For phase II, I will independently investigate whether astrocyte factors whose transcription is upregulated during developmental OL differentiation are sufficient and necessary to promote or inhibit OL differentiation. I propose to test sufficiency in vitro using the BIMA screening assay where OPCs are isolated and seeded onto micropillar arrays then treated with astrocyte factors to determine whether these proteins have an effect on OL differentiation. Then CRISPR/Cas9 technologies will be used to specifically knock out the astroglial factors in vivo and determine whether they are necessary for proper OL differentiation. I believe that these findings will uncover novel regulators of OL differentiation, which could lead to myelin-promoting therapies. In order to successfully achieve my research goals I will learn BIMA screening, electrophysiology, and astrocyte culture techniques under the guidance of my sponsor, Dr. Chan and advisors during phase I. I will also become better trained in crucial career development skills such as communication, leadership, management, and job interviewing skills by participating in UCSF seminars and workshops during phase I. I am confident that this phase I training along with the mentorship of my sponsor and advisors as well as the superior research environment at UCSF will allow me to achieve my career goal of becoming an independent investigator at a top university.

Public Health Relevance

Myelin is important for proper nervous system function, however it is not clear how myelination and the differentiation of oligodendrocytes, the myelin-producing cells of the CNS, are regulated during development. My proposal seeks to 1) uncouple oligodendrocyte differentiation and myelination for the first time and examine the role of dynamic neuronal signaling in regulating both processes, and 2) support a role for astrocytes in regulating oligodendrocyte differentiation. My findings will help to uncover novel, OL differentiation regulators, which could lead to myelin-promoting therapies for the treatment of white matter injury and demyelinating diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K22)
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Study Section
Special Emphasis Panel (ZNS1)
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Morris, Jill A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Mayoral, Sonia R; Etxeberria, Ainhoa; Shen, Yun-An A et al. (2018) Initiation of CNS Myelination in the Optic Nerve Is Dependent on Axon Caliber. Cell Rep 25:544-550.e3