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.

脑衍生的神经营养因子（BDNF）及其接收器（TRKB）在神经元和合成发展以及合成连通性的调节中起关键作用。 BDNF表达或TRKB信号传导的变化深刻影响合成的发展和可塑性。此外，与最佳水平的BDNF和TRKB同工型的偏离对脑功能有严重的后果，因为这会改变合成/神经元功能。 BDNF非常研究，但对其同工型的调节和生物学活性知之甚少。同样，TRKB同工型的调节也不被很好地理解。我的整体研究计划的长期目标是了解神经营养蛋白（NGF和BDNF）的表达和活性如何在转录，翻译后和运输水平上调节其同工型和接收器，以提高我们对突触，可塑性和功能的基本机制的了解。在这项发现赠款的五年中，我将研究调节BDNF和TRKB同工型表达的机制，以及这些同工型如何影响信号传导和突触。 BDNF和TRKB分别在具有不同生物学活性的三种同工型中发现。这些同工型的相对水平在转录后受到调节。但是，机制尚不清楚。我们建议研究特定的miRNA和RNA结合蛋白在TRKB全长同工型（TRKB-FL）的调节中的作用，以及特定蛋白酶在BDNF同工型调节中的作用。此外，我们将研究这些调节因素对培养神经元中BDNF/TRKB信号传导以及脊柱密度和形态的影响。最后，我们将研究截短的BDNF同工型，其受体结合，信号传导和生物学活性未经表征。我们的短期目标是：1）通过检查TRKB RNA结合因子（蛋白质，miRNA）及其对信号传递和脊柱测量的影响来探索TRKB-FL调节； 2）通过特定蛋白质研究BDNF同工型的调节以及对信号转移和脊柱测量的影响； 3）确定截短的BDNF同工型的生物学活性。意义：我的研究计划解决了我们对BDNF生物学的理解中的关键差距。神经营养蛋白的生物合成和功能及其信号在许多级别上的调节，其中一些尚未进行研究。了解ProbDNF的蛋白水解处理，TRKB-FL水平的转录后调控，神经营养蛋白同工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，对我们的突触和大脑发育，调节，调节和功能至关重要。这项研究的结果将导致对每天的大脑功能的新科学和医学理解，例如学习和记忆及其在精神病，神经发育和神经退行性疾病中的失调。