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.

神经元是高度专门化的细胞，构成了大脑回路的基本功能单位，神经元结构和回路的正确发展对大脑的正常功能至关重要。我们建议研究瞬时受体电位Melastatin 7(TRPM7)通道在神经元发育和出生后脑形成中的作用。TRPM7是一种钙离子传导的非选择性二价阳离子通道，与一个活性的α-激酶域融合。TRPM7在包括脑在内的人类组织中普遍表达，并调节多种细胞生物学过程，如镁和钙的动态平衡、细胞的生长和增殖以及胚胎发育。TRPM7基因敲除(KO)对胚胎是致命的，表明TRPM7对发育是必不可少的。然而，我们已经证明TRPM7在脑中表达，并且在体外抑制TRPM7促进轴突生长，并在体内增加神经元对缺氧和缺血的存活。矛盾的是，TRPM7的表达是胚胎发育所必需的，但抑制TRPM7会促进神经突起的生长。然而，TRPM7如何调控神经元发育和出生后脑功能还没有得到充分的研究。由于神经元发育和出生后的大脑功能依赖于一个关键的钙窗口，我假设TRPM7是一种必不可少的蛋白质，调节细胞内钙水平，而细胞内钙水平反过来是神经发育和大脑功能所需的；抑制TRPM7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)。有了合适的工具和试剂，包括我的实验室可以获得的新型选择性TRPM7抑制剂(从我们夏威夷现有的TRPM7合作者那里提取的海洋衍生化合物及其合成类似物)、抗体、TRPM7条件基因敲除(KO)小鼠(可存活/新从我们在日本的合作者那里可以买到，也可以从Jackson实验室买到)和TRPM7激酶抑制剂(商业上可以买到)，以及我在TRPM7方面的丰富经验，我们为未来五年提出了以下三个短期目标和一个未来研究的长期目标。1)研究TRPM7在神经元生长、突触形成和成熟中的作用。2)确定TRPM7的发育特征及其参与神经元发育和突触成熟的相关信号通路。3)体内评价TRPM7对出生后脑功能的影响。我们的长期计划是评估TRPM7在神经生物学功能(如突触可塑性及其相关的认知功能(也包括女性、男性和老年)中的作用。意义：这项工作将有助于我们了解神经发育和脑功能领域中的Trp通道，我们的研究将对HQP的开发有实实在在的好处。