PROJECT SUMMARY/ABSTRACT This proposal outlines a comprehensive five-year mentored career development plan with the goal of preparing the candidate, Sandeep Wontakal, M.D., Ph.D., for an independent academic research career as a physician- scientist. The training plan is designed to acquire and refine skills in three critical aspects essential for a successful career as a physician-scientist: 1) establishing the basis for an independent research program 2) expanding clinical expertise and 3) enhancing mentorship/leadership skills. His strong background in functional genomics from his graduate work and his experience as a board-certified molecular pathologist with expertise in genomic testing of rare disorders, provides a solid foundation upon which the training plan builds. Dr. Wontakal’s long-term research and clinical interest is to decode the information transmitted in the non-coding genome and how mutations in these regions can lead to neurodevelopmental disorders. The scientific aspects of the proposal will be mentored by Dr. Oliver Hobert, Professor and HHMI Investigator, who is a leading neuroscientist with a long track record of mentoring successful trainees. Dr. Wontakal will develop further clinical acumen in identifying pathogenic non-coding mutations under the guidance of the preeminent human geneticist, Dr. David Goldstein, Director of the Institute for Genomic Medicine at Columbia University. An advisory panel of renowned physician- scientists and an expert in RNA neurobiology will also oversee the candidate’s progress and provide guidance. This work will be performed at Columbia University under the auspices of the Department of Biological Sciences, one of the birthplaces of genetics, and the Department of Pathology & Cell Biology, which has a long history of training physician-scientists. The vibrant scientific and clinical environment at Columbia with its world-renowned neuroscience community, will serve as an ideal environment to successfully execute the proposed training plan. Taking advantage of the powerful genetic and cell biological tools available in C. elegans, Dr. Wontakal will study how the long non-coding RNA (lncRNA), lep-5, functions in regulating the timing of neurodevelopment. Lep-5 expression is temporally regulated and preliminary results show lep-5 is required for proper sexual maturation of the male nervous system. Dr. Wontakal has generated several novel strains to determine how the precise spatiotemporal expression of lep-5 is established through studying the following three aims: 1) determine the cis regulatory elements controlling lep-5 expression 2) determine how the transcription factor lin-14 represses lep- 5 expression 3) determine the transcriptional activator(s) of lep-5 expression. This project will enable Dr. Wontakal to gain expertise in genetic analysis, microscopy-based analysis, neurodevelopment, and non-coding RNAs. Importantly, the proposed project has the potential to serve as the foundation ...