Role of TRPM7 and TRPM2 channels in neuronal development and regeneration

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Neurons are highly specialized cells which form the basic and fundamental units in brain circuitry. Proper development of neuronal structure and circuitry will guarantee the normal functions of the brain. In this study, we propose to investigate the role of TRP channels in neuronal development and regeneration. TRPM7, a member of the Transient Receptor Potential (TRP) channel superfamily, is important in embryonic development, cell survival, skeleton formation, and neuronal cell death in hypoxia and ischemia. However, involvement of TRPM7 in neuronal development as well as nerve regeneration has not been investigated. We have shown that TRPM7 and TRPM2 channels are widely expressed in the brain and inhibiting TRPM7 increases neuronal cell survival against ischemia. The paradox is that expression of TRPM7 is required for embryonic development, but suppression of TRPM7 prevents ischemia-induced neuronal cell death in adult. This leads to the postulation that TRPM7 plays a critical role in neuronal development and regeneration by regulating calcium homeostasis. Because neuronal development depends on a critical calcium window, I hypothesize that TRPM7 channels are essential for neuronal development during the embryonic stage; suppressing TRPM7 promotes neuronal regeneration in adult. With suitable reagents for the proposed study, we will pursue our short term objectives to determine: 1) the developmental patterns of TRPM7 and TRPM2 channels in CNS neurons; 2) the role of TRPM7 and TRPM2 in neuronal outgrowth and synapse formation; and 3) the role of TRPM7 and TRPM2 in axonal regeneration in-vitro. We will also study the mechanism of TRPM7 underlying the neuronal development and regeneration. Long term goal of the program is to identify the role of these TRPM channels in regulation of nerve regeneration in-vivo using sciatic nerve injury and regeneration models. Our ultimate goal is to evaluate the physiological and pathophysiological roles of TRPM7 and TRPM2 channels in neuronal development and nerve regeneration. The anticipated research will have benefit for the HQP (highly qualified personnel) training initiative in training our next generation of scientists.