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.

神经元是高度特化的细胞，形成大脑回路的基本功能单元，神经元结构和回路的正确发育对于大脑的正常功能至关重要。我们建议研究瞬时受体电位褪黑蛋白 7 (TRPM7) 通道在神经元发育和出生后大脑形成中的作用。 TRPM7 是一种与活性 α-激酶结构域融合的钙传导非选择性二价阳离子通道。 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，例如镁和钙稳态、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 对于发育至关重要。然而，我们已经证明TRPM7在大脑中表达，并且抑制TRPM7在体外增强神经突生长，并且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 TRPM7 的抑制会增强神经突的生长。然而，TRPM7如何调节神经元发育和出生后大脑功能尚未得到充分研究。由于神经元发育和出生后大脑功能依赖于关键的 Ca2+ 窗口，我推测 TRPM7 是调节细胞内 Ca2+ 水平的重要蛋白质，而细胞内 Ca2+ 水平又是神经发育和大脑功能所必需的。 TRPM7 的抑制可促进神经发育并影响相关的大脑功能和行为结果，特别是出生后神经发育里程碑（代表神经发育反射）。配备合适的工具和试剂，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的类似物，由我们现有的夏威夷 TRPM7 合作者提供）、抗体、TRPM7 条件敲除 (KO) 小鼠（活的/新近从我们现有的 TRPM7 合作者处获得）日本的合作者，也可从杰克逊实验室购买），以及我的实验室可购买的TRPM7激酶抑制剂（可购买），以及我在TRPM7方面的丰富经验，我们提出以下三种未来五年的短期目标和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 发育概况和参与 TRPM7 介导的神经元发育和突触成熟的相关信号通路。 3) 体内评价TRPM7在出生后脑功能中的作用。 我们的长期项目是评估 TRPM7 在神经生物学功能中的作用（例如突触可塑性及其相关的认知功能（也在女性、男性和老年中）。意义：这项工作将有助于我们对 TRP 的了解我们的研究将为 HQP 的发展带来实实在在的好处。