Regulation of BDNF and TrkB Isoforms, their Signaling and Synaptic Modulation

BDNF 和 TrkB 同工型的调节、信号传导和突触调节

• 批准号: RGPIN-2022-05192
• 负责人: Fahnestock, Margaret
• 金额: $ 3.5万
• 依托单位: McMaster University
• 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=763684
• 关键词: Regulation; BDNF; TrkB; Isoforms; their

Brain-derived neurotrophic factor (BDNF) and its receptor (TrkB) play a key role in neuronal and synaptic development and regulation of synaptic connectivity. Changes in BDNF expression or TrkB signalling profoundly impact synaptic development and plasticity. Moreover, deviations from optimal levels of BDNF and TrkB isoforms have severe consequences for brain function, as this can alter synaptic/neuronal function. BDNF is well studied, but less is known about the regulation and biological activity of its isoforms. Similarly, the regulation of TrkB isoforms is not well understood. The long-term goal of my overall research program is to understand how expression and activity of neurotrophins (NGF and BDNF) and their isoforms and receptors are regulated at the transcriptional, post-translational and trafficking levels, to advance our knowledge of basic mechanisms of synapse development, plasticity and function. During the five years of this Discovery Grant, I will study the mechanisms that regulate BDNF and TrkB isoform expression, and how those isoforms impact signaling and synapses. BDNF and TrkB are each found in three isoforms with differing biological activities. Relative levels of these isoforms are regulated post-transcriptionally. However, the mechanisms are unclear. We propose to investigate the role of specific miRNAs and RNA binding proteins in the regulation of the full-length isoform of TrkB (TrkB-FL) and the role of specific proteases in the regulation of BDNF isoforms. Furthermore, we will study the effects of perturbing these regulatory factors on BDNF/TrkB signaling and spine density and morphology in cultured neurons. Lastly, we will study the truncated BDNF isoform, whose receptor binding, signaling and biological activity are uncharacterized. Our Short-Term Objectives are: 1) To explore TrkB-FL regulation by examining TrkB RNA binding factors (protein, miRNA) and their effects on signal transduction and spine measures; 2) To study the regulation of BDNF isoforms by specific proteases and the effects on signal transduction and spine measures; and 3) To determine the biological activity of the truncated BDNF isoform. Significance: My program of research addresses critical gaps in our understanding of BDNF biology. The biosynthesis and function of neurotrophins and how they signal are regulated at many levels, some of which have not been investigated. Understanding the regulation of proteolytic processing of proBDNF, the post-transcriptional regulation of TrkB-FL levels, the biological roles and activities of neurotrophin isoforms, their signalling properties and their effects on neurons and synapses, is critical to our fundamental knowledge of synapse and brain development, regulation and function. The results of this study will lead to new scientific and medical understanding of everyday brain functions such as learning and memory and its dysregulation in psychiatric, neurodevelopmental and neurodegenerative diseases.

脑源性神经营养因子 (BDNF) 及其受体 (TrkB) 在神经元和突触发育以及突触连接调节中发挥着关键作用，BDNF 表达或 TrkB 信号传导的变化深刻影响突触发育和可塑性。 BDNF 和 TrkB 亚型对大脑功能有严重影响，因为它们可以改变突触/神经元功能，但人们对 BDNF 的调节知之甚少。同样，TrkB 亚型的调节也不是很清楚，我整个研究计划的长期目标是了解神经营养因子（NGF 和 BDNF）及其亚型和受体的表达和活性是如何调节的。在转录、翻译后和运输水平上，以增进我们对突触发育、可塑性和功能的基本机制的了解。 在这项发现资助的五年内，我将研究调节机制。 BDNF 和 TrkB 同工型的表达，以及这些同工型如何影响信号传导和突触。这些同工型的相对水平在转录后受到调节。研究特定 miRNA 和 RNA 结合蛋白在 TrkB 全长异构体 (TrkB-FL) 调节中的作用以及特定 miRNA 和 RNA 结合蛋白的作用此外，我们将研究扰乱这些调节因子对培养神经元中 BDNF/TrkB 信号传导以及脊柱密度和形态的影响。我们的短期目标是： 1) 通过检查 TrkB RNA 结合因子（蛋白质、miRNA）及其对信号的影响来探索 TrkB-FL 的调节。转导和脊柱测量；2) 研究特定蛋白酶对 BDNF 同工型的调节以及对信号转导和脊柱测量的影响；以及 3) 确定截短的 BDNF 同工型的生物活性 意义：我的研究计划解决了关键空白。在我们对 BDNF 生物学的理解中，神经营养素的生物合成和功能以及它们的信号如何在多个层面上受到调节，其中一些尚未得到研究。 proBDNF 的蛋白水解加工、TrkB-FL 水平的转录后调节、神经营养蛋白亚型的生物学作用和活性、它们的信号传导特性及其对神经元和突触的影响，对于我们关于突触和大脑发育、调节和发育的基础知识至关重要。这项研究的结果将带来对日常大脑功能（例如学习和记忆）及其在精神、神经发育和神经退行性疾病中的失调的新的科学和医学理解。