Evaluating the role of IL-17A as an orchestrator of peripheral-central cross talk in depressive symptoms

评估 IL-17A 作为抑郁症状中外周-中枢串扰协调者的作用

• 批准号: MR/Z503988/1
• 负责人: Jonathan Cavanagh
• 金额: $ 203.16万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ503988%2F1
• 关键词: Evaluating; role; IL; 17A; orchestrator

SummaryDescribe the research in simple terms in a way that could be publicised to a general audience. This will be made publicly available and Applicants are responsible for ensuring that the content is suitable for publication. No more than, 4000 characters including spaces and returns.Approximately 30-40% of patients with immune-mediated inflammatory diseases (IMIDs), such as Psoriatic disease, experience depression. These negatively affect clinical outcomes, quality of life and treatment adherence. There is accumulating evidence that peripheral inflammation may contribute to the origins of depression. In particular, a) stimulation of the peripheral inflammation results in remitting-relapsing depressive symptoms b) abnormal neural connectivity linked to this depression is correlated with peripheral inflammation and c) biologic therapies targeting specific peripheral inflammation components (cytokines) improve depressive symptoms.In this proposal, Psoriatic disease (PsD) will be our IMID exemplar. In this condition, the IL-23/IL-17 cytokine axis is central to its pathology, as proven by successful application of inhibitors to this pathway. Moreover, this axis has also recently been implicated in the neurobiology of depression in both preclinical and clinical studies. We aim to uncover the mechanisms that underlie depression in the context of IMIDs, delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease. We will test the hypotheses that depression is associated with changes in brain neurochemistry (glutamate) mediated by IL-17A. This in turn drives dysregulation in electrophysiology, function, and structure of brain regions central to reward and emotion. We will use high field strength (7T) magnetic resonance spectroscopy (MRS) to measure brain glutamate with the greatest available precision and magnetic resonance imaging (MRI) to fuse measures of brain function and connections (MRI) with measures of nerve firing (EEG) that will allow us to measure brain networks at optimal levels of resolution in time and space. These imaging and electrophysiological endpoints will be measured at baseline and 6 weeks in 50 PsD patients, randomised 1:1 to treatment with anti-IL17A antibody(secukinumab) or placebo. We predict that anti-IL17A treatment will be associated with reduced brain glutamate expression and amelioration of specific EEG/MRI measures which we consider mechanistic markers of depressive symptoms. In doing so we expect to inform the biological understanding of depression more generally with view to generating urgently needed novel drug targets for this major societal priority.

摘要以可以向一般受众宣传的方式，用简单的术语描述该研究。这将公开，申请人有责任确保内容适合发布。不超过 4000 个字符（包括空格和回车）。大约 30-40% 患有免疫介导炎症性疾病 (IMID)（例如银屑病）的患者患有抑郁症。这些会对临床结果、生活质量和治疗依从性产生负面影响。越来越多的证据表明，外周炎症可能导致抑郁症的发生。特别是，a) 刺激周围炎症会导致缓解-复发性抑郁症状 b) 与这种抑郁相关的异常神经连接与周围炎症相关，c) 针对特定周围炎症成分（细胞因子）的生物疗法可改善抑郁症状。根据建议，银屑病 (PsD) 将成为我们的 IMID 范例。在这种情况下，IL-23/IL-17 细胞因子轴是其病理学的核心，这一点已被成功应用于该途径的抑制剂所证明。此外，该轴最近在临床前和临床研究中也与抑郁症的神经生物学有关。我们的目标是揭示 IMID 背景下抑郁症的机制，通过一项重点免疫干预研究来实现，该研究使用最先进的成像技术在人类免疫疾病的精确特异性治疗性免疫拦截的背景下检查大脑回路。我们将检验抑郁症与 IL-17A 介导的大脑神经化学（谷氨酸）变化有关的假设。这反过来又导致了奖励和情绪核心区域的电生理学、功能和结构失调。我们将使用高场强 (7T) 磁共振波谱 (MRS) 以最高精度测量大脑谷氨酸，并使用磁共振成像 (MRI) 将大脑功能和连接 (MRI) 测量与神经放电 (EEG) 测量融合起来这将使我们能够在时间和空间上以最佳分辨率水平测量大脑网络。这些成像和电生理学终点将在 50 名 PsD 患者的基线和 6 周内进行测量，这些患者按 1:1 的比例随机接受抗 IL17A 抗体（苏金单抗）或安慰剂治疗。我们预测抗 IL17A 治疗将与脑谷氨酸表达减少和特定 EEG/MRI 测量的改善相关，我们认为这些测量是抑郁症状的机制标志。在此过程中，我们希望更广泛地了解抑郁症的生物学知识，以便为这一重要的社会优先事项产生急需的新药物靶点。