Using genome-wide gene expression profiles for early identification of encephalopathic babies at risk of adverse neurological outcomes

目的：我将检查出生条件较差(围产期窒息)的婴儿的身体(宿主)反应(血液中特定基因的活性)是否可以用来识别那些可能患有长期神经残疾的人。背景：我们知道，出生时血液缺乏，大脑供氧受限(围产期窒息)的婴儿，长期脑损伤的风险很高。降低婴儿出生后不久的体温(降温疗法)目前被用作这些婴儿的标准护理，但它并不适用于所有婴儿。多达一半的降温婴儿仍然患有长期残疾，这并不总是与围产期窒息的严重程度直接相关，也不总是与婴儿出生时的身体不适直接相关。快速识别对降温疗法没有反应的婴儿，并了解他们为什么没有反应，对于未来神经保护疗法的发展是至关重要的。我的初步研究表明，围产期窒息会导致血液中遗传活动的独特变化，这与MRI上的脑损伤有关。我现在想测试的假设是，在出生时血液中的基因活动，可以准确地识别患有围产期窒息的婴儿，他们有长期神经残疾的风险。设计和方法：我将在出生后不久收集少量血液，从五家NHS医院招募的总共130名围产期窒息婴儿，为期一年。这些婴儿在18个月大时将接受详细的体检，以检查是否有神经障碍。在我的项目的第一部分，我将使用特定的统计方法来识别与长期残疾(基因签名)相关的最小激活或失活基因集。在第二部分，我将测试这个签名在预测长期残疾方面的准确性。最后，我将研究在患有长期神经残疾的婴儿中激活的基因(通路)的特定生物功能。好处：如果成功，这项工作最终将导致我们识别和治疗围产期窒息婴儿的方式发生范式转变，并将为开发个性化的神经保护疗法开辟一条新的途径。一旦特定的基因表达特征被削减到少数几个基因，它就可以很容易地开发成一种使用聚合酶链式反应(PCR)的床边快速诊断测试。首先，这项测试可以确定哪些婴儿可能对单独的降温治疗没有反应，因此可能需要额外的治疗，但也可以确定不符合当前降温标准的婴儿(例如轻度脑病)，但仍会出现不良后果。这项工作中确定的生物途径将有助于未来神经保护治疗的发展。最后，目前我们只能确定出生时的一小部分婴儿，他们后来发展为脑性瘫痪。一旦被开发为床边测试，它可能会在对这类婴儿进行普遍的新生儿筛查中发挥作用。鉴于每名脑瘫儿童围产期窒息的成本为750,000英磅，任何减少这些数字都将带来巨大的健康和经济利益。患者和公众参与：在项目开发期间与家长团体和Bliss慈善机构的讨论帮助我更多地关注以患者为中心的结果--即早期预测血液测试的不良结果本身对父母并不是特别有用，他们更感兴趣的是这如何改变目前或未来可用的任何治疗方法。在本项目期间，将举行每季度一次的购买力平价会议，协助传播结果并指导今后的研究步骤。我成立了一个由父母组成的咨询小组，他们的孩子患有围产期窒息，他们帮助我设计研究文件。

Aim:I will examine if the body (host) response (activity of specific genes in blood) in babies who are born in a poor condition (perinatal asphyxia), can be used to identify those who are likely to have long-term neurodisability. Background: We know that babies who suffer from a lack of blood flow and restricted oxygen to the brain around the time of birth (perinatal asphyxia), are at a high risk of long term brain damage. Lowering the infant's body temperature (cooling therapy) soon after birth is currently used as standard care for these babies, but it does not work in all of them. Up to half the cooled babies still develop long-term disability, and this is not always directly related to the severity of perinatal asphyxia, or how unwell the babies are at the time of birth. Rapid identification of the babies who will not respond to cooling therapy, and understanding why they do not, is fundamental for the development of future neuroprotective therapies. My preliminary research has shown that a perinatal asphyxia results in unique changes to genetic activity in the blood, which correlates with brain injury on MRI. I now wish to test the hypothesis that gene activity in the blood at the time of birth, can accurately identify babies with perinatal asphyxia who are at risk of long-term neurodisability.Design and Methods: I will collect a small amount of blood soon after birth, from a total of 130 term babies with perinatal asphyxia recruited from five NHS hospitals, over a one-year period. These babies will have a detailed medical examination at 18 months of age, to examine for any neurodisability. In the first part of my project, I will use specific statistical methods to identify a minimal set of activated or deactivated genes that are associated with long-term disability (gene signature). In the second part, I will test the accuracy of this signature in predicting long-term disability. Finally, I will examine the specific biological function of the genes (pathways) activated in babies with long-term neurodisability.Benefits:If successful, this work will eventually lead to a paradigm shift in the way we identify and treat babies with perinatal asphyxia, and will open up a new avenue for developing individualised neuroprotective therapies. Once the specific gene expression signature is trimmed down to a handful of genes, it can then be easily developed as a rapid bedside diagnostic test, using polymerise chain reaction (PCR). In the first instance, this test can identify babies who may not respond to cooling therapy alone, and hence may need additional therapies, but also infants who do not meet the current cooling criteria (for example mild encephalopathy), but still develop adverse outcomes. The biological pathways identified in this work will help the development of future neuroprotective treatments. Finally, at present we are able to identify only a small proportion of babies at the time birth, who later develop cerebral palsy. Once developed as a bedside test, it may have a role in universal neonatal screening for such infants. Given that perinatal asphyxia can cost £750,000 for each child with cerebral palsy, any reduction in these numbers would have substantial health and economic benefits. Patient and Public Involvement:Discussions with parent groups and the Bliss charity during the project development helped me to focus more on patient centred outcomes - i.e. an early prediction of adverse outcome from a blood test by itself was not particularly useful for parents, and they were much more interested in how this could modify any current or future treatments available. Quarterly PPI meetings will be conducted during the course of this project, assisting with dissemination of the results and guiding future steps of the research. I have set up an advisory group of parents whose children had perinatal asphyxia and they helped me with designing study documents.