Role of TRPM7 and TRPM2 channels in neuronal development and regeneration

神经元是高度特化的细胞，构成了大脑回路的基本单元。神经元结构和神经回路的正常发育是大脑正常功能的保证。在本研究中，我们拟探讨TRP通道在神经元发育和再生中的作用。TRPM7是瞬时受体电位（TRP）通道超家族的成员，在胚胎发育、细胞存活、骨骼形成以及缺氧和缺血时神经元细胞死亡中起重要作用。然而，TRPM7在神经元发育和神经再生中的作用尚未被研究。我们发现TRPM7和TRPM2通道在大脑中广泛表达，抑制TRPM7可提高神经元细胞抗缺血的存活率。矛盾的是，TRPM7的表达是胚胎发育所必需的，但抑制TRPM7可防止成人缺血诱导的神经元细胞死亡。这导致TRPM7通过调节钙稳态在神经元发育和再生中起关键作用的假设。由于神经元的发育依赖于一个关键的钙窗口，我假设TRPM7通道对胚胎阶段的神经元发育至关重要；抑制TRPM7可促进成人神经元再生。通过合适的试剂，我们将追求我们的短期目标，以确定：1)中枢神经系统神经元中TRPM7和TRPM2通道的发育模式；2) TRPM7和TRPM2在神经元生长和突触形成中的作用；3) TRPM7和TRPM2在体外轴突再生中的作用。我们还将研究TRPM7在神经元发育和再生中的作用机制。该项目的长期目标是利用坐骨神经损伤和再生模型，确定这些TRPM通道在体内调节神经再生中的作用。我们的最终目的是评估TRPM7和TRPM2通道在神经元发育和神经再生中的生理和病理生理作用。预期的研究将有利于HQP（高素质人才）培训计划，以培养我们的下一代科学家。

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.