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。我们之前已经在慢性胎盘功能不全（妊娠期间氧气和营养水平降低）的豚鼠模型中显示，神经元及其之间的连接减少。这可能是由于新产生的神经元数量减少（神经发生），或神经元死亡增加（凋亡），或两者兼而有之。为了开发治疗策略来改善大脑发育并最终恢复功能，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）确定次优的胎儿环境是否通过影响神经发生、细胞凋亡或两者来减少神经元数量，2）研究可能影响细胞凋亡和神经发生的受损脑环境的变化，3）确定次优的胎儿环境是否对成人神经发生有长期影响，4）确定促红细胞生成素治疗是否对成人神经发生有长期影响。促红细胞生成素（Epo）是一种天然存在的激素，可以解决大脑发育和功能的缺陷。促红细胞生成素是一个令人兴奋的候选药物，因为它是，或正在被用于治疗中风和新生儿窒息的过程中。促红细胞生成素也被证明可以防止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最大限度地发挥其潜力，并减少个人和整个社会在怀孕期间出现问题时必须承担的巨大社会、经济和教育负担，那么了解脑损伤的机制并找到有效的治疗方法是一个至关重要的努力领域。

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.