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Role of TRPM7 and TRPM2 Channels in Neuronal Development and Regeneration

TRPM7 和 TRPM2 通道在神经元发育和再生中的作用

基本信息

批准号：
RGPIN-2016-04574
负责人：
Sun, HongShuo
金额：
$ 2.26万
依托单位：
University of Toronto
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2016
资助国家：
加拿大
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615151
关键词：
Role TRPM7 TRPM2 Channels Neuronal

项目摘要

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.

神经元是形成脑回路中的基本功能单元的高度特化的细胞，并且神经元结构和回路的适当发育对于脑的正常功能是必不可少的。我们建议研究瞬时受体电位（TRP）通道在神经元发育和再生中的作用，特别关注TRPM 7及其密切相关的TRPM 2通道。TRPM 7和TRPM 2是可渗透Ca 2+的非选择性阳离子通道，在多种生理功能中发挥重要作用，包括细胞存活和增殖。TRPM 7敲除（KO）是胚胎致死的。然而，我们已经表明TRPM 7通道在脑中表达，并且抑制这些通道增加了神经元对缺氧（Sun lab，Mol Brain 2015，8：11）和缺血的存活（Sun等人，Nat Neurosci 2009; 12：1300-7）。自相矛盾的是，TRPM 7的表达是胚胎发育所必需的，但抑制或抑制TRPM 7可防止新生儿缺氧诱导的神经元细胞死亡和成人缺血诱导的神经元细胞死亡。这导致我们假设TRPM 7通过在常氧和缺氧条件下差异调节Ca 2+稳态在神经元发育和再生中起关键作用。然而，TRPM 7如何参与神经元发育和再生尚未得到充分研究。由于神经元的发育和再生取决于一个关键的Ca 2+窗口，我假设TRPM 7通道是一个必不可少的蛋白质调节Ca 2+水平，反过来，需要在正常和缺氧条件下，通过不同的下游信号通路的神经元发育和再生。相反，抑制TRPM 7可以促进神经元细胞增殖、存活、生长和再生。必要的合适工具和试剂包括选择性TRPM 7和TRPM 2抑制剂、siRNA、CRISPR（TRPM 7构建体）、抗体、TRPM 2敲除（KO）小鼠（存活的）和TRPM 7激酶KO，以及我实验室可获得的TRPM 7和TRPM 2的诱导型KO小鼠（正在开发中）。结合我在TRPM 7的丰富经验，我们建议在未来五年内开展以下三个短期项目和一个长期项目： 1)探索TRPM 7和TRPM 2在常氧和缺氧条件下神经元生长、成熟和突触形成中的作用。 2)确定在常氧和缺氧条件下TRPM 7和TRPM 2通道介导的脑神经元发育和成熟中涉及的信号通路。 3)评估TRPM 7和TRPM 2在体外和体内神经元再生中的作用。我们的长期项目是评估TRPM 7和TRPM 2在神经元再生中的作用。重要性：这项工作将有助于我们在神经元发育和再生领域的TRP通道的知识，我们的研究将对HQP的发展有切实的好处。