Defects in the nonsense-mediated mRNA decay (NMD) pathway have recently been implicated in multiple neuropsychiatric diseases. However, this pathway has not been well studied in the brain and disruption of NMD in neurons has not been characterized. We recently discovered a novel regulatory role of the NMD pathway in the nervous system. Through coupling to alternative splicing regulation, NMD controls the expression level of postsynaptic density protein 95 (PSD-95), an essential scaffold protein of the excitatory PSD. This mechanism of regulation is similar to the output of transcriptional control, but it is unclear what other natural neuronal transcripts are regulated by NMD. My long term goal is to understand the role of NMD- mediated regulation in the nervous system, and how errors in NMD can lead to neuropsychiatric disorders. The objective of this proposal is to characterize fundamental developmental defects resulting from deficiencies in the NMD pathway and systematically identify physiological NMD substrates in rodent neurons. I have already generated an NMD deficient mouse model and developed various techniques for this proposal. Guided by strong preliminary data, I will pursue two specific aims: 1) Genome-wide identification of NMD targets important for neuronal development;2) Characterize the physiological requirement for the NMD pathway during development. Based on preliminary data, two important aspects of synapse development, spine morphology and synaptic expression of glutamate receptors, will be examined thoroughly in NMD deficient neurons both in vivo and in vitro. Identification of natural NMD substrates in neurons will shed light on how frequently NMD is used as an active regulatory pathway of gene expression rather than a passive quality-control mechanism. Knowledge about the genetic roles and specific targets of NMD in brain provides a novel perspective for understanding the pathogenesis of various neuropsychiatric diseases and may help point to the common targets/pathways for therapeutic intervention. I have a background in both cellular neuroscience and RNA molecular biology. I am in a unique position to contribute to the proposed research area. To further prepare myself for my long-term research goal, I plan to seek training that will complement my existing technical skills and further develop my professional skills. UCLA has a highly collaborative environment ideal to this project and for me to achieve these goals. My mentor, Dr. Douglas Black, is one of the world-class experts in alternative splicing regulation. I also have an advisory committee that consists of Dr. Kelsey Martin, Dr. Tom O'Dell, and Dr. William Yang and provide complementary inputs on neuroscience. My mentor team has a detailed plan to facilitate my research progress and scientific career development. In summary, my educational and research experience together with a strong and supportive mentoring team make me an ideal candidate for this research project and the K99/R00 award.
The proposed research is relevant to public health because it will begin to reveal the roles of the nonsensemediated mRNA decay pathway in neural development, and potentially in the pathogenesis of mental disorders. This research is relevant to the NIH's mission of developing fundamental knowledge that will help to reduce the burdens of human disability.