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High-probability grants
According to our matching algorithm, Jason J Yi is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2021 |
Yi, Jason J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Understanding the Mechanisms of Ube3a Regulation in Neuronal Development
Abstract. UBE3A is a gene that encodes a HECT (Homologous to E6AP C-terminus) domain E3 ubiquitin ligase linked to numerous developmental and psychiatric disorders. Loss of function of the maternally derived UBE3A enzyme causes Angelman syndrome whereas gain of function, due to duplication or triplication of UBE3A, is linked to a broad range of disorders including Dup15q syndrome, schizophrenia, and mood disorders. These observations strongly suggest that bi-directional changes in UBE3A activity contribute to neuropsychiatric pathology. However, the mechanisms that regulate UBE3A activity remain poorly understood. The primary goal of our proposed research is to uncover mechanisms of UBE3A regulation, that when faulty, can lead to aberrant gain or loss of UBE3A function. In preliminary work, we developed a high-throughput assay to assess the functional consequence of non-truncating UBE3A missense variants. This screen identified numerous novel loss of function mutations, as well as gain of function mutations that hyperactivate UBE3A activity well above wild type (WT) enzyme levels. These results provide deep structure-function information that we can now leverage to uncover mechanisms of UBE3A regulation. This proposal aims to, 1) create a complete functional catalogue of known missense variants identified in individuals, 2) utilize structure-function analyses to identify mechanisms that can lead to both aberrant gain and loss of enzyme function, and 3) leverage biochemical insights to engineer proteins that can target UBE3A activity. The molecules generated from our work will be applied to examine whether alteration of UBE3A activity can rescue synaptic phenotypes observed in mice harboring hyperactivating mutations in UBE3A. If successful, our work will provide new biochemical insights and tools that will make it possible to target UBE3A for therapeutic intervention in various neuropsychiatric disorders.
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