Sexual dimorphism in immune mediated preterm brain injury.

在世界各地，每年有1500万婴儿早产(怀孕37周前)。重症监护的进步提高了早产儿的存活率，但在此期间，发育中的大脑仍然容易受到伤害。幸存者的脑损伤可能导致学习、行为、记忆和沟通方面的困难。这些问题终生存在，而且没有治疗方法可以改善长期结果。与相同孕龄出生的女婴相比，男婴患脑瘫、智力残疾和精神障碍的风险更高。原因尚不清楚，但有几条证据表明，在发育中的大脑对早期感染的破坏性影响的脆弱性方面存在性别差异。需要进行人体研究来促进我们对潜在生物学的理解，以便开发成功的治疗方法来保护发育中的大脑。通过结合干细胞技术、先进的脑部扫描(MRI)和尸检脑组织的实验方法，我将确定感染如何影响早期大脑发育，并确定性别差异。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，这种细胞被称为有机体。为了了解感染对男性和女性婴儿大脑发育的不同影响，我还将使用先进的新生儿大脑核磁共振扫描和死亡早产儿的脑组织来研究大脑的生长和发育。这项研究计划的首要目标是找出促进早产后大脑健康发育的性别特异性治疗方法。

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.