2017 — 2019 |
Whitman, Mary Catherine |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Oculomotor Axon Guidance in Normal and Abnormal Development @ Boston Children's Hospital
This proposal describes a 3-year training program for the development of an academic career focused on understanding the molecular mechanisms of strabismus and ocular motility disorders. I am a pediatric ophthalmologist at Boston Children's Hospital (BCH) and Harvard Medical School (HMS), currently training in the Harvard Vision Clinical Scientist Development Program (K12). I wish to continue my research and career development to prepare for an independent research career. My long-term goals include understanding the molecular basis of complex strabismus, elucidating fundamental mechanisms of axon guidance, and ultimately devising new treatments for strabismus and ocular motility disorders, such as aberrant regeneration. The proposed research program focuses on identifying new molecular pathways important for axon guidance of the oculomotor nerve and additional genetic causes of Congenital Fibrosis of the Extraocular Muscles (CFEOM). Dr. Elizabeth Engle will serve as mentor. She is a world expert on the development of the oculomotor system and has a proven track record of productivity and mentorship. An advisory committee including David Hunter, Daniel MacArthur, and Larry Benowitz will guide my research and career development. The project will take place in the rich research environment of BCH, with access to the resources of HMS, Massachusetts Eye and Ear Infirmary, and the Broad Institute. There are extensive opportunities to attend and present at lab meetings, departmental seminars, national meetings, and didactic courses. The first experimental approach uses a novel midbrain-orbit embryonic slice assay I developed, in which the developing oculomotor nerve is time-lapse imaged as it grows towards the orbit. To identify signaling pathways important in oculomotor growth and guidance the cultures are treated with small molecule inhibitors of cell- surface receptors. Candidate receptors will be chosen based on transcriptional profiling of motor neurons at E10.5 and E11.5 (unpublished data). The role of molecules that perturb guidance in the slice assay will be defined in vivo by examining mouse models for axon guidance defects and aberrant innervation. Proof of concept has been established using an inhibitor of CXCR4 signaling, AMD3100. Preliminary data in vivo confirms oculomotor axon growth dorsally rather than ventrally, and this pathway will be further examined. The second approach seeks to relate these findings to human disorders of ocular motility, particularly CFEOM. Whole genome sequencing (WGS) is underway on 48 pedigrees with genetically unsolved CFEOM, and will be analyzed in collaboration with Daniel MacArthur's team at the Broad Institute. Variants in pathways that perturb axon guidance in the slice assay will be prioritized in the analysis. Conversely, variants identified in the WGS will be tested in the slice assay to help determine pathogenicity. Through these approaches, we will identify new pathways important in axon guidance, opening new areas of research. The proposal addresses an understudied area of clinical need while preparing me for a successful career as a clinician-scientist.
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