An ex-vivo placental perfusion system to study materno-fetal biology

描述(由申请人提供)：解决自闭症谱系障碍(ASD)异质性的研究项目标题：一个研究母胎生物学的体外胎盘灌流系统。这笔赠款将专注于开发和验证一个模型系统，以检查母婴相互作用的变化对胎儿大脑发育的影响。我们认为，母体免疫挑战和应激源对胎儿大脑发育的影响是胎盘中发生的母胎相互作用改变的直接结果。已知胎盘中循环的母体色氨酸代谢是保护胎儿免受母体免疫所必需的。我们的初步结果表明，在妊娠的早期关键期，色氨酸胎盘代谢的另一条途径也为胎儿循环提供5-羟色胺，因此可能对正常的胎儿大脑连接至关重要。提出了一个新的体外双灌流模型系统，这将使我们能够测试母体免疫挑战直接影响胎盘色氨酸代谢途径的可能性，扰乱胎儿5-羟色胺的供应，最终影响子宫内的大脑连接。由于胎盘代谢功能在怀孕期间发生变化，我们假设母体因素对胎儿大脑发育的影响程度将取决于时机、挑战的性质以及母亲和后代的遗传易感性。我们的体外模型系统将提供一种独特的方法来剖析每个因素对色氨酸胎盘代谢的影响，以及随后它对影响与ASD相关的神经生物学功能的贡献，如胎儿大脑回路的形成。使用小鼠胎盘将使我们能够在与ASD相关的广泛遗传模型中以及在不同的妊娠阶段测试胎盘新陈代谢改变的影响。这是一个关键的进步，因为它提供了独特的机会来确定母源性神经递质、细胞因子、激素和药物如何影响与ASD有关的5HT相关回路和其他回路的发展。 公共卫生相关性：产前期间的母婴互动对儿童的大脑发育至关重要。母体疾病会增加包括自闭症在内的神经精神疾病的风险，可能会损害这些相互作用。我们建议设计和实施一项新技术，该技术将提供独特的机会来确定母亲衍生的分子，如神经递质、细胞因子、激素和药物如何到达胎儿大脑，并影响与ASD有关的电路的发育。

DESCRIPTION (provided by applicant): Research to Address the Heterogeneity in Autism Spectrum Disorders (ASD) Project title: An ex-vivo placental perfusion system to study materno-fetal biology. This grant will focus on developing and validating a model system to examine the effects of alterations in materno-fetal interactions on fetal brain development. We propose that the impact of maternal immune challenges and stressors on fetal brain development is a direct consequence of altered materno-fetal interactions taking place in the placenta. Circulating maternal tryptophan metabolism in the placenta is known to be required for protecting the fetus from maternal immunity. Our preliminary results suggest that, during an early critical period of gestation, an alternative pathway of tryptophan placental metabolism also provides serotonin to the fetal circulation and therefore may be critical for normal fetal brain wiring. Advancing a new ex vivo dual perfusion model system proposed here will enable us to test the possibility that maternal immune challenges directly impact multiple placental metabolic pathways for Trp disrupting fetal supply of 5-HT and ultimately brain wiring in utero. Since placental metabolic functions change during pregnancy, we hypothesize that the degree to which maternal factors impact fetal brain development will depend on a combination of timing, nature of the challenges and also genetic susceptibility of the mother and offspring. Our ex vivo model system will provide a unique way to dissect the effect of each factor on tryptophan placental metabolism and subsequently its contribution to impacting neurobiological functions relevant to ASD such as fetal brain circuits formation. The use of mouse placentas will enable us to test the impact of altered placental metabolism in a wide array of genetic models relevant to ASD and at different stages of gestation. This is a critical advance, as it provides unique opportunities to determine how maternally derived neurotransmitters, cytokines, hormones and drugs impact the development of 5HT-relevant and other circuits that have been implicated in ASD. PUBLIC HEALTH RELEVANCE: Maternal-fetal interactions during the prenatal period are essential for brain development in the child. Maternal illness which increases the risk for neuropsychiatric disorders, including ASD, may impair these interactions. We propose to design and implement a new technology that will provide unique opportunities to determine how maternally derived molecules such as neurotransmitters, cytokines, hormones and drugs reach the fetal brain and impact the development of circuits that have been implicated in ASD.