Fetal reprogramming by gestational intermittent hypoxia impairs respiratory neuromotor control in adult offspring

项目摘要 众所周知，子宫内环境，特别是母体免疫激活， 关键的胎儿生理系统，但这在呼吸神经控制的背景下评价不佳。 间歇性缺氧（IH）是睡眠呼吸障碍（SDB）的标志， 炎症，我们最近开始认识到，母亲在怀孕期间SDB有深刻的 对新生儿的负面影响。然而，到目前为止，几乎没有什么是已知的，关于这些是否 成年后才开始发育。此外，尚不清楚母体IH是否足以引起胎儿 重新编程，或者如果成年后代呼吸控制系统是目标。阻塞性睡眠呼吸暂停 (OSA)SDB的一种形式，似乎是可遗传的，但特定的易感基因突变（除了那些导致 颅面畸形）尚未确定，表明表观遗传可能起作用。后生 改变是许多形式的遗传细胞记忆的基础， 反应，提示SDB的遗传易感性可能是从母亲传过来的 通过胎儿免疫系统的表观遗传重编程传给子宫内的后代。总体假设 指导这项工作的是，妊娠期间歇性缺氧（GIH）使成年后代本身易于发生SDB， 表观遗传修饰CNS固有固有免疫细胞（小胶质细胞）的活性。使用啮齿动物模型， GIH，我们的初步数据表明，成年GIH后代有增加中枢性呼吸暂停在推定期间， 睡眠和对呼吸神经活动的反复减少的代偿可塑性受损。 暴露于慢性IH和代偿性IH可加重GIH诱导的中枢性呼吸暂停增加， 局部给予抗炎药可恢复对复发性呼吸暂停的反应（目的1），提示 神经炎症在GIH损伤中的重要作用。此外，我们的初步数据表明， 小胶质细胞对免疫系统攻击的反应在成年GIH后代中被夸大（“引发”）， 与暴露于缺氧的小胶质细胞培养物中致敏炎症基因处的组蛋白标记富集一致。 因此，我们假设GIH通过改变小胶质细胞甲基化组来引发炎症基因转录（Aim 2）。我们的研究将测试几种策略，以扭转呼吸控制障碍造成的胎儿 先天免疫细胞的重编程（Aim 3）。如果我们的假设是正确的，这些研究将确定 首次妊娠期IH：1）在代偿性呼吸神经可塑性中产生终身缺陷， 复发性神经性呼吸暂停，2）在成年期易患呼吸不稳定，3）造成终身慢性 小胶质细胞炎症与小胶质细胞甲基化组的表观遗传变化相关。考虑到病理性的 成人SDB发病率的上升及其显著的发病率，我们的研究对于确定潜在的 新疗法可以针对这些机制来预防或纠正重编程成人的睡眠障碍。

PROJECT SUMMARY The in utero environment, and in particular, maternal immune activation, is well-known to permanently reprogram critical fetal physiological systems, but this has been poorly evaluated in the context of respiratory neural control. Intermittent hypoxia (IH), a hallmark of sleep disordered breathing (SDB), causes both central and peripheral inflammation, and we have recently begun to appreciate that maternal SDB during pregnancy has profound negative consequences to the newborn. However, to date, virtually nothing is known regarding whether these detriments extend into adulthood. Further, it is unknown whether maternal IH is sufficient to cause fetal reprogramming, or if the adult offspring respiratory control system is a target. Strikingly, obstructive sleep apnea (OSA), a form of SDB, appears to be heritable, but specific predisposing gene mutations (beyond those causing craniofacial abnormalities) have not been identified, indicating a likely role for epigenetic inheritance. Epigenetic alterations underlie many forms of heritable cellular memory including those regulating the innate immune response, suggesting the intriguing possibility that heritable susceptibility for SDB may be passed from mother to offspring in utero via epigenetic reprogramming of the fetal immune system. The overarching hypothesis guiding this work is that gestational intermittent hypoxia (GIH) predisposes adult offspring to SDB themselves by epigenetically modifying the activities of CNS resident innate immune cells (microglia). Using a rodent model of GIH, our preliminary data suggest that adult GIH offspring have increased central apneas during presumptive sleep and impaired compensatory plasticity in response to recurrent reductions in respiratory neural activity. GIH-induced increases in central apneas is exacerbated by exposure to chronic IH, and compensatory responses to recurrent apneas is restored by local administration of anti-inflammatory drugs (Aim 1), suggesting an essential role for neural inflammation in GIH impairments. Moreover, our preliminary data suggest that microglial responses to an immune system challenge are exaggerated (“primed”) in adult GIH offspring, consistent with histone mark enrichment at primed inflammatory genes in microglial cultures exposed to hypoxia. Thus, we hypothesize that GIH primes inflammatory gene transcription by altering the microglial methylome (Aim 2). Our studies will test several strategies to reverse respiratory control impairments caused by fetal reprogramming of innate immune cells (Aim 3). If our hypotheses are correct, these studies will identify for the first time that gestational IH: 1) creates life-long deficits in compensatory respiratory neuroplasticity triggered by recurrent neural apnea, 2) predisposes to unstable breathing in adulthood, and 3) creates life-long, chronic microglial inflammation associated with epigenetic changes in the microglial methylome. Given the pathological rise in adult SDB incidence, and its significant morbidities, our studies will be essential for identifying underlying mechanisms that can be targeted by novel therapies to prevent or correct SDB in reprogrammed adults.