Role of uptake2 in neuroprotective signaling

Project Summary/Abstract This project is a diversity supplement to the parent project R16NS129675 (Nonpeptide neurotrophic mechanisms in spinal cord repair). The supplement will extend the scope of the parent project and provide training opportunities for an outstanding master’s degree candidate in preparation for subsequent enrollment in a doctoral program. The overall goal of the parent project is to increase understanding of neuroregenerative mechanisms and uncover novel pharmacological targets for the treatment of spinal cord injury (SCI). Following rational selection and screening of small-molecule compounds, we identified several candidates having the ability to boost neurotrophic signaling and promote regrowth of damaged nerve cells in a tissue culture model. While the parent project will explore the molecular mechanisms of action of these compounds in neuroregenerative models, the present supplementary project will focus on testing some of the compounds in a cellular neuroprotection model. Specifically, the supplement project will address the question whether the ability of the compounds to provide neuroprotection in cultured cells is dependent on prior cellular internalization of the compounds through the postsynaptic transporter fondly designated as Uptake2, and then probe the differential role of transcripts mediating CDP-diacylglycerol synthesis in the microsomal and mitochondrial compartments. By addressing the neuroprotective mechanism of the compounds, the parent project will gain a more comprehensive perspective on the development prospects of the compounds. Beyond the planned experiments and anticipated results, the trainee will have opportunity for structured learning experiences as part of the master’s program in translational medicine. Overall, this supplementary project is expected to tangibly contribute to diversifying and expanding the biomedical research and practice workforce given its expected preparation of the trainee for onward access and success in doctoral studies.