Sexual dimorphism in immune mediated preterm brain injury.

在世界各地，每年有1500万婴儿过早出生（妊娠37周之前）。重症监护的进步提高了早产儿的存活率，但发育中的大脑在此期间仍然容易受到伤害。幸存者的脑损伤可能导致学习、行为、记忆和交流困难。这些问题会持续终生，并且没有治疗方法可以改善长期预后。与同胎龄出生的女婴相比，男婴患脑瘫、智力残疾和精神疾病的风险更高。其原因尚不清楚，但有几条证据表明，发育中的大脑对早期感染的破坏性影响的脆弱性存在性别差异。人类的研究是必要的，以促进我们对潜在生物学的理解，以开发成功的治疗方法，以保护发育中的大脑。通过结合干细胞技术，先进的脑扫描（MRI）和死后脑组织的实验方法，我将确定感染如何影响早期大脑发育和两性差异。我将使用人类干细胞产生男性和女性免疫细胞（小胶质细胞），研究它们对感染的反应，并研究它们如何与3D迷你大脑中发育中的脑细胞（神经元）相互作用，称为类器官。为了了解感染如何对发育中的男女婴儿大脑产生不同的影响，我还将使用先进的新生儿大脑MRI扫描和无法存活的早产儿的脑组织研究大脑的生长和发育。该研究计划的总体目标是确定性别特异性疗法，以促进早产后大脑的健康发育。

Around the world, 15 million babies are born too soon (before 37 weeks gestation) each year. Advances in intensive care have improved survival rates for preterm infants but the developing brain remains vulnerable to injury during this period. Brain injury among survivors can result in difficulties with learning, behaviour, memory and communication. These problems persist lifelong and there are no treatments available to improve long-term outcomes.Male infants have an increased risk of developing cerebral palsy, intellectual disability, and psychiatric disorders when compared with female infants born at the same gestational age. The reasons for this are unknown but several lines of evidence suggest there are sex differences in the vulnerability of the developing brain to the damaging effects of infection in early life. Human studies are needed to advance our understanding of the underlying biology in order to develop successful treatments to protect the developing brain.Through an experimental approach combining stem cell technology, advanced brain scans (MRI) and post-mortem brain tissue, I will determine how infection affects early brain development and characterise sex differences. I will use human stem cells to generate male and female immune cells (microglia), study their responses to infection, and examine how they interact with developing brain cells (neurons) in 3D mini brains, called organoids. To understand how infection can affect the developing brain differently in male and female infants, I will also study brain growth and development using advanced neonatal brain MRI scans and brain tissue from preterm infants who do not survive.The overarching aim of this programme of research is to identify sex-specific therapies that promote healthy brain development after preterm birth.