Receptor Tyrosine Kinase Transactivation in Neuronal Signalling, Stress, and Survival

脑细胞(神经元)通过蛋白质“受体”相互交流。蛋白质受体的主要类型包括G蛋白偶联受体(GPCRs)、受体酪氨酸激酶(RTK)和离子通道，如N-甲基-D-天冬氨酸(NMDA)受体。一种类型的受体的信号如何受到其他类型受体(受体串扰)的影响还知之甚少。我们的实验室致力于更好地了解一种名为“RTK反式激活”的特定类型的串扰，它是如何影响神经元活动的，它在应对神经元应激和促进神经元存活方面的作用。这项研究是必要的，这样我们才能充分了解健康神经元、受损神经元或承受压力的神经元的大脑功能的复杂性。描述RTK反式激活研究的大部分工作都是描述性的，并在非神经元模型中进行。我们的研究目标之一是研究RTK在神经元(原代培养和体外脑片)和新的神经元样细胞系(如海马源性Ht22细胞系)中的反式激活途径。除了回答有关RTK反式激活的几个基本问题外，开发这些新的模型系统将对神经科学中的其他研究人员有价值，包括那些有兴趣将Ht22细胞系用作海马状模型的人。除了RTK反式激活的基本特征外，我们的第二个目标是研究RTK反式激活对神经元信号、活性和存活的影响，重点是NMDA受体信号和兴奋毒性(当NMDA受体过度激活时)。我们已经证明，5-HT7受体能够通过血小板衍生生长因子(PDGF)受体和TrkB受体的反式激活来调节NMDA受体信号转导，减少兴奋性毒性。在一些细胞和组织中，包括心肌细胞、血管平滑肌细胞、肺和肾上皮细胞，以及在白细胞中，RTK信号和RTK的反式激活都会因应激或组织损伤而改变。我们的第三个目标是确定RTK反式激活在神经元应激反应中的作用。神经元应激是否像在其他类型的细胞中观察到的那样启动RTK反式激活通路？在神经元应激中，特定的GPCR-RTK反式激活通路是否被破坏？确定RTK信号的变化范围和神经元应激的反式激活将提供对神经元对应激的细胞反应的更强有力的理解。由于我们的研究涉及多种技术、模型系统以及与其他研究人员的合作，我实验室的学生将获得一套多样化的技能，使他们能够在学术和工业环境中继续推进知识。我们的研究结果将影响多个学科的科学家和研究人员，包括基础和应用神经科学、压力和应激神经生物学，以及神经精神病学和神经学的研究人员。

Brain cells (neurons) communicate with one another using protein "receptors". Major types of protein receptors include G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and ion channels such as the N-methyl-D-aspartate (NMDA) receptor. How the signalling of one type of receptor is influenced by the others (receptor cross-talk) is less understood. Our lab works to better understand a specific type of cross-talk called "RTK transactivation", how it influences neuronal activity, its role in responding to neuronal stress, and promoting neuronal survival. This research is needed so we can fully understand the complexity of brain function in both healthy neurons, damaged neurons, or neurons experiencing stress. Much of the work describing RTK transactivation research has been descriptive and carried out in non-neuronal models. One of our research objectives is to characterize RTK transactivation pathways in both neurons (primary cultures and ex vivo brain slice) and in novel neuronal-like cell lines such as the hippocampus-derived Ht22 cell line. In addition to answering several fundamental questions about RTK transactivation, developing these new model systems will be valuable to other researchers in neuroscience, including those interested in employing the Ht22 cell line as a hippocampal-like model. Beyond the basic characterization of RTK transactivation, our second objective is to study the consequences of RTK transactivation on neuronal signalling, activity, and survival with a focus on NMDA receptor signalling and excitotoxicity (when NMDA receptors are over-activated). We have demonstrated that the 5-HT7 receptor is able to regulate NMDA receptor signalling and reduce excitotoxicity via platelet-derived growth factor (PDGF) receptor and TrkB receptor transactivation. In several cells and tissues, including cardiac myocytes, vascular smooth muscle cells, pulmonary and renal epithelial cells, and in white blood cells, RTK signalling, and RTK transactivation specifically, is altered by stress or tissue damage. Our third objective is to determine the role of RTK transactivation in the neuronal response to stress. Does neuronal stress initiate RTK transactivation pathways as observed in other cell types? Are specific GPCR-RTK transactivation pathways disrupted in neuronal stress? Determining the scope of changes in RTK signalling and transactivation in neuronal stress will provide a more robust understanding of the cellular responses to stress in neurons. As our research involves multiple techniques, model systems, and collaborations with other researchers, students in my lab will gain a diverse set of skills that will allow them to continue to advance knowledge in academic and industrial settings. The outcomes of our research will impact scientists and researchers across several disciplines, including basic and applied neuroscience, stress and stress neurobiology, as well as researchers in neuropsychiatry and neurology.