Role of TRPM7 in Neuronal Development and Neurobiology Functions

TRPM7 在神经元发育和神经生物学功能中的作用

• 批准号: RGPIN-2022-04589
• 负责人: Sun, HongShuo
• 金额: $ 2.04万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765819
• 关键词: Role; TRPM7; Neuronal; Development; Neurobiology

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.

神经元是形成脑回路基本功能单位的高度特化的细胞，神经元结构和回路的正常发育对大脑的正常功能至关重要。我们建议研究瞬时受体电位美拉他汀7 （TRPM7）通道在神经元发育和出生后脑形成中的作用。TRPM7是一种钙传导非选择性二价阳离子通道，融合了一个活性的a激酶结构域。TRPM7在包括大脑在内的人体组织中普遍表达，并调节各种细胞生物学过程，如镁和钙的稳态、细胞生长和增殖以及胚胎发育。TRPM7敲除（KO）是胚胎致死的，表明TRPM7对发育至关重要。然而，我们已经证明TRPM7在大脑中表达，抑制TRPM7可以促进体外神经突起的生长，并增加体内缺氧和缺血时神经元的存活。矛盾的是，TRPM7的表达是胚胎发育所必需的，但抑制TRPM7可促进神经突的生长。然而，TRPM7如何调节神经元发育和产后脑功能尚未得到充分研究。因为神经元发育和产后脑功能依赖于一个关键的Ca2+窗口，我假设TRPM7是调节细胞内Ca2+水平的必需蛋白，而细胞内Ca2+水平反过来又需要神经发育和脑功能；TRPM7的抑制促进神经发育并影响相关的脑功能和行为结果，特别是出生后神经发育里程碑（代表神经发育反射）。使用合适的工具和试剂，包括新型选择性TRPM7抑制剂（waixenicin A，一种海洋衍生化合物及其合成类似物，来自我们夏威夷现有的TRPM7合作者），抗体，TRPM7条件敲除（KO）小鼠（可行/新从我们现有的日本合作者那里获得，杰克逊实验室也有市售），TRPM7激酶抑制剂（市售），以及我在TRPM7方面的丰富经验，我们提出未来五年的三个短期目标和未来研究的一个长期目标。1)探讨TRPM7在神经元生长、突触形成和成熟中的作用。2)确定TRPM7的发育特征及TRPM7介导的神经元发育和突触成熟的相关信号通路。3)在体内评估TRPM7在出生后脑功能中的作用。我们的长期项目是评估TRPM7在神经生物学功能（如突触可塑性及其相关的认知功能）中的作用（也适用于女性和男性以及老年）。意义：本工作将有助于我们在神经发育和脑功能领域对TRP通道的认识，我们的研究将对HQP的发展有切实的好处。