The overarching objectives of this K99/ROO application are to transition to an independent investigator position, and to identify and characterize genetic loci with a role in inherited peripheral neuropathies. My long-term career goal is to establish myself as an independent investigator in the field of neurogenetics. Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. About 2.4% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. A more complete understanding of the genes implicated in peripheral neuropathies will provide insight into the etiology of these diseases and aid the development of more efficient therapies. Two genes encoding enzymes that charge tRNA molecules with their cognate amino acids (ARSs) have been implicated in inherited peripheral neuropathies. My current research involves determining the molecular pathology associated with mutations in one of these genes (GARS). This work has revealed that the majority of mutations are associated with a loss of function. Furthermore, wild-type GARS becomes associated with granules in human peripheral nerve axons. I thus hypothesize that GARSassociated granules are required in axons for local tRNA charging, and that other ARSs likely play a role in inherited peripheral neuropathies. To address this I will: (Specific Aim 1) establish the protein-content and function of GARS-associated granules in axons;and (Specific Aim 2) screen all human ARS genes for mutations in DMA samples isolated from patients with inherited peripheral neuropathy. Another area of my current research involves studying the transcriptional regulation of the SOX10 locus, which encodes a transcription factor with an important role in peripheral nerve development and function. Importantly, SOX10 transcriptionally regulates certain genes that are commonly mutated in patients with peripheral neuropathy. I thus hypothesize that SOX10 transcriptionally regulates other genes important for peripheral nerve health. To address this I will (Specific Aim 3) identify and characterize SOX10-target genes in the peripheral nervous system. Completing these Specific Aims will provide: (i) a better understanding of the role of GARS in peripheral nerve axons;(ii) knowledge about the role of all ARS genes in inherited peripheral neuropathies; and (iii) a more complete panel of genes transcriptionally regulated by SOX10 in peripheral nerves. The training (K99) portion of this award will be mentored by Dr. Eric D. Green at the National Human Genome Research Institute. Dr. Green is a recognized leader in the fields of human genetics and comparative genomics.
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