Role of the JAK/STAT pathway in LTD

JAK/STAT 通路在 LTD 中的作用

• 批准号: BB/K019899/1
• 负责人: Graham Collingridge
• 金额: $ 64.77万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK019899%2F1
• 关键词: Role; JAK; STAT; pathway; LTD

Information storage in the brain depends on changes in the efficiency by which nerve cells (neurons) communicate. This occurs at specialised structures (synapses) via the release of a chemical neurotransmitter and its detection by receptor proteins, a process called synaptic transmission. The strength of this communication can be increased or decreased, depending on the patterns of synaptic activation, i.e. synaptic plasticity. In general, synaptic transmission can be increased by the process known as long-term potentiation (LTP) or decreased by the process known as long-term depression (LTD). The best established forms of synaptic plasticity involve the activation of one class of glutamate receptor, the NMDA receptor, which leads to alterations in the number of another class of glutamate receptor, the AMPA receptor, at synapses. We recently identified that the JAK2/STAT3 pathway is involved in LTD. This pathway is well known for regulating gene expression during inflammation or cell proliferation, for example. Dysregulation of this pathway can lead to auto-immune diseases or cancer and has also been linked recently to Alzheimer's disease. The aim of the proposed project is to find the mechanisms by which JAK2 and STAT3 are involved in LTD in the hippocampus, a brain region critically involved in learning and memory. Indeed, the way JAK2 is activated and how it leads to a reduction in AMPA receptor number at synapses remain to be defined. Furthermore, against expectation, we found that, during the first few hours after induction of LTD, the action of STAT3 is independent of gene regulation but involves one or more unknown targets in the cytoplasm that are important to identify. Since STAT3 translocates to the nucleus after LTD, it may nevertheless regulate the expression of genes that are important for the maintenance of LTD at later stages of the process. The present proposal aims at answering these and related questions in order to identify how this pathway is involved in LTD. We believe this project will lead to a better understanding of synaptic plasticity and the associated diseases but also bring more clues about the role of JAK2 and STAT3 in cell biology in general. This project could also potentially lead to the discovery of new JAK2 and STAT3 effectors which could be used as therapeutic targets. Indeed, these molecules have been targeted for the treatment of some auto-immune diseases (such as myelofibrosis and rheumatoid arthritis) and cancer (such as lymphomas). Clinical trials for JAK and STAT inhibitors are under way. However, the role of JAK and STAT is important for different physiological processes and the mediation of different cytokine receptors (e.g., Il-6, IL-12, Interferons). Therefore, a strong or complete inhibition of this pathway is not desirable and can lead to haematological disorders, dizziness and headaches. Finding new JAK2 or STAT3 effectors is a first step to extend our knowledge about this pathway in the brain which should help in the identification of new therapeutic targets for a range of disorders.

大脑中的信息存储取决于神经细胞（神经元）交流效率的变化。这发生在专门的结构（突触），通过释放化学神经递质和受体蛋白检测，这一过程称为突触传递。这种通信的强度可以增加或减少，这取决于突触激活的模式，即突触可塑性。一般来说，突触传递可以通过称为长时程增强（LTP）的过程增加或通过称为长时程抑制（LTD）的过程减少。突触可塑性的最佳形式涉及一类谷氨酸受体（NMDA受体）的激活，这导致突触处另一类谷氨酸受体（AMPA受体）数量的改变。我们最近发现JAK 2/STAT 3通路参与LTD。例如，该通路在炎症或细胞增殖期间调节基因表达是众所周知的。这一途径的失调可导致自身免疫疾病或癌症，最近还与阿尔茨海默病有关。该项目的目的是寻找JAK 2和STAT 3参与海马LTD的机制，海马是一个与学习和记忆密切相关的大脑区域。事实上，JAK 2被激活的方式以及它如何导致突触处AMPA受体数量的减少仍有待确定。此外，出乎意料的是，我们发现，在LTD诱导后的最初几个小时内，STAT 3的作用不依赖于基因调控，但涉及细胞质中一个或多个未知的靶标，这些靶标对于识别很重要。由于STAT 3在LTD后易位到细胞核，因此它可能仍然调节在该过程的后期阶段对LTD的维持很重要的基因的表达。本提案旨在回答这些问题和相关问题，以确定该途径如何参与LTD。我们相信，该项目将有助于更好地了解突触可塑性和相关疾病，同时也为JAK 2和STAT 3在细胞生物学中的作用提供更多线索。该项目还可能导致发现新的JAK 2和STAT 3效应子，可用作治疗靶点。事实上，这些分子已经被靶向用于治疗一些自身免疫疾病（如骨髓纤维化和类风湿性关节炎）和癌症（如淋巴瘤）。JAK和STAT抑制剂的临床试验正在进行中。然而，JAK和STAT的作用对于不同的生理过程和不同细胞因子受体（例如，IL-6、IL-12、干扰素）。因此，强烈或完全抑制这一途径是不可取的，并可能导致血液疾病，头晕和头痛。寻找新的JAK 2或STAT 3效应子是扩展我们对大脑中这一通路的了解的第一步，这将有助于确定一系列疾病的新治疗靶点。

项目成果

Rapid regulation of endoplasmic reticulum dynamics in dendritic spines by NMDA receptor activation.

• DOI: 10.1186/s13041-014-0060-3
• 发表时间: 2014-08-19
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Ng AN;Doherty AJ;Lombroso PJ;Emptage NJ;Collingridge GL
• 通讯作者: Collingridge GL