ZNF804A: connecting a confirmed schizophrenia risk gene to neuronal, network and behavioural function

ZNF804A：将已确认的精神分裂症风险基因与神经元、网络和行为功能联系起来

• 批准号: G1002179/1
• 负责人: Lawrence Wilkinson
• 金额: $ 111.51万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1002179%2F1
• 关键词: ZNF804A; connecting; confirmed; schizophrenia; risk

Millions of motorists set out every morning and the majority of them manage to reach their destinations without incident. But with such a complex and busy network of roads, it does not take much for rush hour to go wrong: just one breakdown can mean gridlock, particularly if the system is already made vulnerable by roadworks. Brains are similar: normally they work well when left to their own devices, but complex diseases like schizophrenia (which afflicts around 1 in 100 people) emerge from very subtle causes, particularly in patients already made vulnerable, by drug abuse for example. Unfortunately, effective treatment of schizophrenia is still hampered by the fact that we do not know exactly what these complex causes are.We do know that the most important vulnerability factor is family history. If you inherit a faulty secondhand car ? even if it works at first ? it may be you that breaks down and causes rush hour chaos. And if someone in your family has schizophrenia, genes you inherit from them increase your risk of developing the disease. Identifying these genetic faults is therefore critical, since it allows us to identify people at risk, to understand disease mechanism by studying the mechanics of what particular genes contribute to brain function, and hopefully to develop better treatments.Our recent work surveying around 60,000 people, their genes and their diseases has identified variations in one particular gene consistently linked to schizophrenia. But for this information to be useful, we need to understand what the gene does and why particular versions of it put people at risk of developing debilitating psychotic, depressive and learning problems. To do this, we have engineered mice that also carry variations in the mouse equivalent of the schizophrenia-linked gene. This project will study brain structure, behaviour and brain activity of these mice to see if they share any features in common with schizophrenia patients (e.g. changes in anxiety, learning and memory, sleep). Although schizophrenia cannot be modeled fully in mice, showing that subtle variations of this gene cause symptoms reminiscent of the disease in animal models will provide direct evidence that it is the culprit. These models can then be used to develop and test better therapies that keep brain traffic flowing smoothly.

每天早晨，成千上万的驾车者都会出发，大多数人都设法到达目的地而没有发生任何事件。但是，凭借如此复杂而繁忙的道路网络，高峰时间不需要太多出错：只有一个故障可能意味着僵局，尤其是如果该系统已经被道路工程造成了攻击。大脑是相似的：通常，当将其留在自己的设备上时，它们的工作效果很好，但是像精神分裂症这样的复杂疾病（苦难约100人中有1人）从非常微妙的原因中出现，尤其是在已经被药物滥用造成的患者中，尤其是在患者中。不幸的是，我们不知道这些复杂的原因是什么是对精神分裂症的有效治疗。我们确实知道，最重要的脆弱性因素是家族史。如果您继承了有故障的二手车？即使起初有效？可能是您分解并导致高峰时段混乱。而且，如果您家庭中的某人患有精神分裂症，那么您从中继承的基因会增加您患疾病的风险。因此，识别这些遗传缺陷至关重要，因为它使我们能够通过研究特定基因对脑功能的贡献的力学来识别有危险的人，并希望开发更好的治疗方法，从而了解疾病的机制。我们最近对60,000人，他们的基因及其疾病进行了调查，他们的基因及其疾病已经确定了一个特定基因的变体，并与Schizizophrenia息息相关。但是，要使这些信息有用，我们需要了解基因的作用，以及为什么它的特定版本会使人们处于衰弱的精神病，抑郁和学习问题的风险。为此，我们已经设计了小鼠，这些小鼠在相当于精神分裂症相关基因的小鼠中也有变化。该项目将研究这些小鼠的大脑结构，行为和大脑活动，以查看它们是否与精神分裂症患者共同（例如焦虑，学习和记忆，睡眠）的任何特征。尽管精神分裂症不能在小鼠中完全建模，但表明该基因的细微变化会导致症状让人联想起动物模型中的疾病，这将直接证明这是罪魁祸首。然后，这些模型可用于开发和测试更好的疗法，以使大脑流量顺畅。