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

描述（由申请人提供）：研究自闭症谱系障碍（ASD）的异质性项目名称：用于研究母胎生物学的离体胎盘灌注系统。该资助将侧重于开发和验证一个模型系统，以检查母胎相互作用改变对胎儿大脑发育的影响。我们提出，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后果。在胎盘中循环母体色氨酸代谢被认为是保护胎儿免受母体免疫所必需的。我们的初步结果表明，在妊娠早期的关键时期，胎盘色氨酸代谢的另一种途径也为胎儿循环提供血清素，因此可能对正常的胎儿大脑线路至关重要。本文提出的一种新的体外双灌注模型系统将使我们能够测试母体免疫挑战直接影响色氨酸的多种胎盘代谢途径的可能性，这些途径破坏了胎儿5-羟色胺的供应，并最终破坏了子宫内的大脑线路。由于胎盘代谢功能在怀孕期间会发生变化，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间、挑战的性质以及母亲和后代的遗传易感性。我们的离体模型系统将提供一种独特的方法来分析每个因素对色氨酸胎盘代谢的影响，以及随后它对与ASD相关的神经生物学功能（如胎儿脑回路形成）的影响。小鼠胎盘的使用将使我们能够在一系列与ASD相关的遗传模型中以及在妊娠的不同阶段测试胎盘代谢改变的影响。这是一个关键的进展，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.