Role of TRPM7 and TRPM2 Channels in Neuronal Development and Regeneration

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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 (TRP) channels in neuronal development and regeneration with specific interest in TRPM7 and its closely related TRPM2 channels. TRPM7 and TRPM2 are non-selective cation channels permeable to Ca2+ and play an important role in various physiological functions, including cell survival and proliferation. TRPM7 knockout (KO) is embryonic lethal. However, we have shown that TRPM7 channels are expressed in the brain, and inhibiting these channels increases neuronal survival to hypoxia (Sun lab, Mol Brain 2015, 8:11) and ischemia (Sun et al., Nat Neurosci 2009; 12:1300-7), both in vitro and in vivo. The paradox is that expression of TRPM7 is required for embryonic development, but inhibition or suppression of TRPM7 prevents hypoxia-induced neuronal cell death in neonates and ischemia-induced neuronal cell death in adults. This leads to our postulating that TRPM7 plays a critical role in neuronal development and regeneration by differentially regulating Ca2+ homeostasis under normoxic and hypoxic conditions. However, how TRPM7 is involved in neuronal development and regeneration has not been fully investigated. Because neuronal development and regeneration depends on a critical Ca2+ window, I hypothesize that the TRPM7 channel is an essential protein regulating Ca2+ levels that are, in turn, needed for neuronal development and regeneration under normal and hypoxic conditions via differential downstream signal pathways. Conversely, inhibition of TRPM7 may promote neuronal cell proliferation, survival, outgrowth and regeneration. The requisite suitable tools and reagents include selective TRPM7 and TRPM2 inhibitors, siRNA, CRISPR (TRPM7 construct), antibodies, TRPM2 knockout (KO) mice (viable), and TRPM7 kinase KO, as well as inducible KO mice for both TRPM7 and TRPM2 (under development) available to my lab. Together with my extensive experience in TRPM7, we propose the following three short-term projects and one long-term project over the next five years:***1) Explore the role of TRPM7 and TRPM2 in neuronal outgrowth, maturation and synapse formation in normoxic and hypoxic conditions.***2) Determine the signal pathways involved in the TRPM7 and TRPM2 channels mediated neuronal development and maturation in brain neurons in normoxic and hypoxic conditions. ***3) Evaluate the role of TRPM7 and TRPM2 in neuronal regeneration in vitro and in vivo. ***Our long-term project is to evaluate the role of TRPM7 and TRPM2 in neuronal regeneration.***Significance: This work will contribute to our knowledge of the TRP channels in the field of neuronal development and regeneration, and our research will have tangible benefits for HQP development.**