Compromised fetal brain development: neurogenesis and the potential for therapeutic intervention.

怀孕期间胎儿大脑缺氧被认为是新生儿脑损伤的主要原因。其中一些婴儿会出现发育和行为问题，包括脑瘫、精神分裂症和癫痫。目前，没有有效的治疗方法来纠正大脑发育的这些变化，这是当今围产期医学的主要挑战之一。我们之前在豚鼠慢性胎盘功能不全（怀孕期间氧气和营养水平降低）模型中表明，神经元及其之间的连接减少。这可能是由于新生成的神经元数量减少（神经发生），或神经元死亡（细胞凋亡）增加，或两者兼而有之。为了开发治疗策略来改善大脑生长并最终恢复功能，我们必须了解导致这些大脑变化的机制。在这个项目中，我们将使用我们的豚鼠模型：1)确定次优胎儿环境是否通过影响神经发生、细胞凋亡或两者同时影响而减少神经元数量；2)研究受损脑环境中可能影响细胞凋亡和神经发生的变化；3)确定次优胎儿环境是否对成人神经发生有长期影响；4)确定用促红细胞生成素（Epo）治疗是否可以解决脑发育和功能缺陷。促生成素是一种令人兴奋的候选药物，它正在被用于治疗中风和新生儿窒息。Epo也被证明可以预防脑损伤后的神经元死亡和促进神经发生。如果我们要帮助婴儿开发他们最大的潜力，减少巨大的社会、经济和教育负担，了解脑损伤的机制并找到有效的脑损伤治疗方法，这是一个至关重要的努力领域。当怀孕期间出现问题时，这些负担必须由个人和整个社会承担。

Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns. Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of chronic placental insufficiency (reduced oxygen and nutrient levels during pregnancy) that there is a reduction in neurons and in the connections between them. This may result from a reduction in number of newly generated neurons (neurogenesis), or an increase in neuronal death (apoptosis), or both. To develop therapeutic strategies to improve brain growth and ultimately functional recovery, we must understand the mechanisms which lead to these brain changes. In this project, we will use our guinea pig model to: 1) determine whether a suboptimal fetal environment decreases neuronal numbers by influencing neurogenesis, apoptosis or both, 2) study changes in the compromised brain environment which are likely to influence apoptosis and neurogenesis, 3) determine whether a suboptimal fetal environment has long-term effects on adult neurogenesis and 4) determine whether treatment with erythropoietin (Epo), a naturally occurring hormone, can resolve deficits in brain development and function. Epo is an exciting candidate as it is, or is in the process of being used to treat stroke and newborn asphyxiation. Epo has also been shown to prevent neuronal death and promote neurogenesis following brain injury. Understanding the mechanisms and finding effective treatments for brain damage is a vital area of endeavour if we are to help infants develop their maximum potential and reduce the enormous social, economic and educational burden which must be borne by the individual and society in general when things go wrong during pregnancy.