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

目的：我将研究身体（宿主）反应（血液中特定基因的活性）是否可以用于识别那些出生条件较差的婴儿（围产期窒息），以确定那些可能患有长期神经残疾的婴儿。背景：我们知道，婴儿在出生时缺乏血液流动和大脑缺氧（围产期窒息），长期脑损伤的风险很高。目前，在婴儿出生后不久降低婴儿体温（降温疗法）是这些婴儿的标准护理方法，但并不是对所有婴儿都有效。多达一半的低温婴儿仍然会发展为长期残疾，这并不总是与围产期窒息的严重程度或婴儿出生时的不适直接相关。快速识别对冷却疗法没有反应的婴儿，并了解他们没有反应的原因，是未来神经保护疗法发展的基础。我的初步研究表明，围产期窒息会导致血液中基因活动的独特变化，这与MRI显示的脑损伤有关。我现在想验证一个假设，即出生时血液中的基因活性，可以准确地识别出围产期窒息的婴儿，他们有长期神经功能障碍的风险。设计与方法：我将在出生后不久收集少量血液，从五家NHS医院招募130名围产期窒息的足月婴儿，为期一年。这些婴儿将在18个月大时接受详细的医学检查，以检查是否有任何神经残疾。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相关的激活或失活基因的最小集合（基因签名）。在第二部分，我将测试这个特征在预测长期残疾方面的准确性。最后，我将研究在长期神经残疾的婴儿中激活的基因（途径）的特定生物学功能。益处：如果成功，这项工作将最终导致我们识别和治疗围产期窒息婴儿的方式的范式转变，并将为开发个性化神经保护疗法开辟新的途径。一旦特定的基因表达特征被削减到少数几个基因，它就可以很容易地发展为一种快速的床边诊断测试，使用聚合链反应（PCR）。首先，该测试可以识别出可能对单独冷却疗法没有反应的婴儿，因此可能需要额外的治疗，但也可以识别出不符合当前冷却标准（例如轻度脑病）但仍会产生不良后果的婴儿。在这项工作中确定的生物学途径将有助于未来神经保护治疗的发展。最后，目前我们只能识别出一小部分在出生时患上脑瘫的婴儿。一旦发展为床边测试，它可能在这类婴儿的普遍新生儿筛查中发挥作用。鉴于每个脑瘫儿童的围产期窒息费用为75万英镑，减少这些数字将带来巨大的健康和经济效益。患者和公众参与：在项目开发过程中，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——也就是说，通过血液测试本身对不良结果的早期预测对父母来说并不是特别有用，他们更感兴趣的是如何改变当前或未来可用的治疗方法。在本项目进行期间，将召开季度PPI会议，协助传播结果并指导未来的研究步骤。我成立了一个由孩子围产期窒息的家长组成的咨询小组，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.