Cellular drivers of type I interferon-mediated neuropathology

I 型干扰素介导的神经病理学的细胞驱动因素

• 批准号: MR/Y001958/1
• 负责人: Sophie Hambleton
• 金额: $ 160.57万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001958%2F1
• 关键词: Cellular; drivers; type; interferon; mediated

The immune system has evolved primarily to protect us against infection. Yet if not properly controlled, the potent responses that it unleashes can lead to inadvertent damage to normal cells and tissues. An example is a family of immune substances known as 'interferons'. Interferons are chemical messengers released by virally exposed cells, signalling neighbouring cells to adopt a state that blocks viral infection and spread. Interferons also regulate other immune functions and slow the growth of cancer cells. As such, they have been developed clinically to treat a range of diseases. Whilst these properties are beneficial, exposure to too much interferon, for too long, can be harmful. The brain appears especially vulnerable to the damaging effects of interferon. This has been suggested by the careful study of patients with a group of severe genetic diseases known as 'type I interferonopathies', which are largely untreatable, leading to neurological illness and disability and premature death. The type I interferonopathies are associated with rare 'spelling errors' in DNA (mutations) that result in the interferon system being turned on inappropriately. We have recently discovered a new form of type I interferonopathy associated with mutation of a gene called STAT2 that plays a critical role in signalling immediately downstream of the type I interferon receptor. The mutated STAT2 can't deliver negative feedback on the receptor that activates it, so generates an abnormally strong and long inflammatory response to interferon. This new disease provides evidence to support the notion that interferon is neurotoxic but also raises questions about precisely how interferon leads to brain damage. Answering these questions should help us to identify better treatments for patients with this devastating diagnosis. It will also likely help us to understand how interferon might contribute to various more common disease states, such as dementia or stroke, in which it has been implicated. In unpublished studies we have developed a rodent model of STAT2-associated type I interferonopathy. The animals show similar clinical features to patients. This is an important advance, providing an experimental model in which to investigate how interferon leads to the abnormalities seen in patients and how to intervene with treatment(s). In this model, we have identified problems affecting a range of brain cell types, suggesting that interferon causes disease through complex actions in multiple cell types. In this project we will use cutting-edge methods to express the abnormal STAT2 gene in different brain cell types and then establish the consequences for brain function using clinical tests and detailed study of tissues. We will investigate the underlying molecular processes using techniques to measure gene expression of individual cells. This will help us to develop theories about the way that interferons operate to produce disease. To test these, we will make use of human stem cells that we can turn into different brain cell types in a dish. We have produced stem cells bearing the mutant STAT2 gene for use in these experiments. By comparing the behaviour of cell types bearing the mutant STAT2 with identical cells lacking the mutant STAT2, we will learn ways in which interferons perturb the normal function of different cell types in the brain. Together, these results will explain how interferons lead to brain damage and give insight into the generation of type I interferonopathy. It is possible that this occurs through the direct action of interferons on these brain cell types, or toxic effects may be indirect. This information is relevant to the development of treatments, especially as we move toward the next generation of treatments for genetic diseases such as gene therapy or cell transplantation. Our findings may even help to inform the safer clinical use of interferons.

免疫系统主要是为了保护我们免受感染。然而，如果无法正确控制，它释放的有效反应可能会导致对正常细胞和组织的无意损害。一个例子是一个被称为“干扰素”的免疫物质家族。干扰素是由病毒暴露的细胞释放的化学信使，信号邻近细胞采用阻断病毒感染和扩散的状态。干扰素还调节其他免疫功能并减慢癌细胞的生长。因此，它们已在临床上开发以治疗各种疾病。尽管这些特性是有益的，但暴露于太多的干扰素，但太长时间可能是有害的。大脑似乎特别容易受到干扰素的破坏作用。仔细研究了一组被称为“ I型干扰素病”的患者的仔细研究，这些患者在很大程度上无法治疗，从而导致神经系统疾病，残疾和过早死亡。 I型干扰素病与DNA（突变）中罕见的“拼写错误”有关，导致干扰素系统不适当地打开。最近，我们发现了一种与称为STAT2的基因突变相关的I型I型干扰素病，该突变在立即在I型干扰素受体下游的信号传导下起着关键作用。突变的STAT2无法对激活它的受体产生负面反馈，因此会对干扰素产生异常强的炎症反应。这种新疾病提供了支持干扰素神经毒性的观念的证据，但也提出了有关干扰素如何导致脑损伤的问题。回答这些问题应该有助于我们为这种毁灭性诊断的患者确定更好的治疗方法。它也可能会帮助我们了解干扰素如何对涉及痴呆症或中风等各种更常见的疾病状态做出贡献。在未发表的研究中，我们开发了与STAT2相关的I型I型干扰素病的啮齿动物模型。这些动物显示出与患者相似的临床特征。这是一个重要的进步，提供了一个实验模型，以研究干扰素如何导致患者出现的异常以及如何干预治疗。在此模型中，我们发现了影响一系列脑细胞类型的问题，这表明干扰素通过多种细胞类型的复杂作用引起疾病。在这个项目中，我们将使用尖端方法在不同的脑细胞类型中表达异常的STAT2基因，然后使用临床测试和组织的详细研究来确定脑功能的后果。我们将使用技术测量单个细胞的基因表达研究基础分子过程。这将有助于我们发展有关干扰素生产疾病的方式的理论。为了测试这些，我们将利用人类干细胞，可以在菜肴中变成不同的脑细胞类型。我们已经产生了带有突变体STAT2基因的干细胞，用于这些实验。通过比较带有突变体STAT2的细胞类型的行为与缺乏突变体STAT2的相同细胞，我们将学习干扰子扰动大脑中不同细胞类型的正常功能的方法。这些结果共同解释了干扰素如何导致脑损伤，并深入了解I型干扰素病的产生。这可能是通过干扰素对这些脑细胞类型的直接作用发生的，或者有毒作用可能是间接的。该信息与治疗的发展有关，尤其是当我们迈向下一代遗传疾病（例如基因治疗或细胞移植）的治疗方法时。我们的发现甚至可能有助于告知干扰素的更安全的临床使用。