The role of chromatin remodelling factors in cerebellar development and autism

自闭症可能是一种毁灭性的疾病，没有合适的治疗方法。自闭症影响了个人在社会中发挥作用所需的一些核心行为特征，即社会互动以及语言和非语言交流。受自闭症影响的儿童往往表现出有限的，重复的行为和兴趣模式。在过去的十年中，被诊断患有自闭症谱系障碍（ASD）的人数急剧增加，目前的估计表明，高达1/110的人口可能受到影响。自闭症的原因尚不清楚，如果没有这些知识，找到治疗这种疾病或改善自闭症儿童生活的新方法的希望有限。自闭症是一种复杂的遗传疾病;许多可能使儿童易患自闭症的遗传异常已经被确定，但我们对这些遗传风险因素如何在大脑发育过程中引起变化从而导致自闭症行为的知识非常有限。对自闭症儿童的研究表明，在发育过程中，大脑某些部分的生长可能会改变。大脑中最常受影响的部分是小脑。小脑控制运动，但也是大脑其他部分的重要调节器，包括参与社会认知和语言发展的区域。目前还不知道小脑的这些缺陷是如何产生的，也不知道小脑缺陷对自闭症特征行为的影响。目前，直接解决这一问题的最佳方法是研究大脑发育以及大脑发育改变对自闭症相关基因突变小鼠行为的行为后果。本课题组一直在研究CHD 7基因在脑发育中的功能。CHD 7突变时会导致CHARGE综合征，这是一种复杂的人类综合征，儿童除了自闭症症状外，还患有一系列出生缺陷。我们最近确定了CHD 7在小脑发育和生长中的重要作用。当CHD 7发生突变时，我们观察到小脑特定区域的缺陷与自闭症有关。本项目的目的是确定这些缺陷的确切原因，并发现在缺少CHD 7时存在缺陷的特定过程。这些知识可能有助于在未来确定针对这些过程的特定疗法。此外，我们已经使用了强大的遗传方法在小鼠中产生突变体，其中CHD 7专门从发育中的小脑中去除。这些新的小鼠突变体将使我们能够确定这些小脑缺陷在多大程度上导致自闭症症状。此外，我们将采取同样的方法来确定一个名为CHD 8的相关基因的功能，该基因最近被证明与人类自闭症密切相关，但没有任何CHARGE综合征典型的出生缺陷。这些研究将使我们能够深入了解自闭症的具体原因。这项研究将使我们能够找到自闭症研究中几个重要问题的答案。我们将确定CHD 7和CHD 8突变在大脑发育过程中引起问题的原因，这些因素控制小脑生长和发育的确切机制，我们将确定小脑缺陷在多大程度上导致自闭症的一些核心行为症状。总之，我们的研究将显著提高我们对自闭症原因的理解，并确定小脑缺陷在自闭症发展中的重要性。我们的发现将为未来预测、诊断和治疗自闭症的特定方面提供重要的知识来源。

Autism can be a devastating condition for which no suitable treatment exists. Autism affects some of the core behavioural features an individual needs to function in society, namely social interaction and both verbal and non-verbal communication. Children affected by autism often demonstrate restricted, repetitive patterns of behaviour and interests. The number of individuals diagnosed with Autism Spectrum Disorder (ASD) has increased dramatically over the last decade and current estimates suggest that up to 1/110 of the population may be affected. The causes of autism are not known and without this knowledge, there is limited hopes of finding novel ways of treating this condition or improving the lives of autistic children. Autism is a complex genetic condition; many genetic abnormalities that can predispose a child to autism have been identified, but our knowledge on how these genetic risk factors can cause changes during brain development to result in autistic behaviour is extremely limited. Studies in autistic children have suggested that the growth of certain parts of the brain might to be altered during development. The part of the brain that appears to be affected most often is the cerebellum. The cerebellum controls movement, but also functions as an important modulator of other parts of the brain, including regions involved in social cognition and language development. It is not known how these defects in the cerebellum arise, nor is it known what the effects of cerebellar defects are on behaviours characteristic of autism. Currently, the best way to address this question directly is to study brain development and the behavioural consequences of altered brain development on behaviour in mice that have mutations in autism-associated genes. Our group have been investigating the functions of the CHD7 gene in brain development. CHD7 causes CHARGE syndrome when mutated, a complex human syndrome where children suffer from a range of birth defects in addition to autistic symptoms. We recently identified essential roles for CHD7 in the development and growth of the cerebellum. When CHD7 is mutated, we observe defects in specific areas of the cerebellum that have been linked to autism. The aim of this project will be to identify the exact causes of these defects and to uncover the specific processes that are defective when CHD7 is absent. This knowledge may help define specific therapies to target these processes in the future.In addition, we have used the powerful genetic methods available in the mouse to produce mutants in which CHD7 is removed specifically from the developing cerebellum. These new mouse mutants will enable us to determine to what extent these cerebellar defects cause autistic symptoms. Furthermore, we will take the same approach to determine the function of a related gene called CHD8, which was recently shown to be very strongly associated with autism in the human population, but without any of the birth defects typical of CHARGE syndrome. These studies will allow us to hone in on the specific causes of autism. This research will allow us to find answers to several important questions in autism research. We will identify the reasons why mutations in CHD7 and CHD8 can cause problems during brain development, the exact mechanisms whereby these factors control growth and development of the cerebellum and we will determine to what extent cerebellar defects are responsible for some of the core behavioural symptoms characteristic of autism. Taken together, our research will significantly improve our understanding of the causes of autism and define the importance of cerebellar defects in the development of autism. Our findings will create an important source of knowledge upon which future attempts to predict, diagnose, and possibly treat specific aspects of autism could be based.