Role of TRPM7 in Neuronal Development and Neurobiology Functions

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Neurons are highly specialized cells that form the basic functional units in brain circuitry, and proper development of neuronal structure and circuitry is essential for normal function of the brain. We propose to investigate the role of Transient Receptor Potential Melastatin 7 (TRPM7) channels in neuronal development and postnatal brain formations. TRPM7 is a calcium-conducting non-selective divalent cation channel fused with an active a-kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 knockout (KO) is embryonic lethal, indicating that TRPM7 is essential for development. However, we have shown that TRPM7 is expressed in the brain, and inhibiting TRPM7 enhanced neurite outgrowth in vitro, and increases neuronal survival to hypoxia and ischemia in vivo. The paradox is that expression of TRPM7 is required for embryonic development, but inhibition of TRPM7 enhance neurite outgrowth. However, how TRPM7 regulates the neuronal development and postnatal brain functions has not been fully investigated. Because neuronal development and postnatal brain functions depend on a critical Ca2+ window, I hypothesize that the TRPM7 is an essential protein regulating intracellular Ca2+ levels that are, in turn, needed for neurodevelopment and brain functions; inhibition of TRPM7 promotes neurodevelopment and affects the related brain functional and behavioural outcomes especially the postnatal neurodevelopmental milestones (representing as the neurodevelopmental reflexes). With suitable tools and reagents, including novel selective TRPM7 inhibitors (waixenicin A, a marine-derived compound and its synthesized analogs from our existing TRPM7 collaborators in Hawaii), antibodies, TRPM7 conditional knockout (KO) mice (viable / newly available from our existing collaborator in Japan and also commercially available from The Jackson Laboratory), and TRPM7 kinase inhibitor (commercially available) available to my lab, and my extensive experience in TRPM7, we propose the following three short-term objectives for the next five years and one long-term objective for the future study. 1) Investigate the role of TRPM7 in neuronal outgrowth, synapse formation and maturation.. 2) Determine the TRPM7 developmental profile and related signal pathways involved in the TRPM7 mediated neuronal development and synaptic maturation. 3) Evaluate the role of TRPM7 in postnatal brain functions in vivo. Our long-term project is to evaluate the role of TRPM7 in in neurobiology functions (such as synaptic plasticity and its associated cognitive functions (also in female and male and old age too). Significance: This work will contribute to our knowledge of the TRP channels in the field of neurodevelopment and brain functions, and our research will have tangible benefits for HQP development.