Mechanisms and rescue of craniosynostosis associated with gene-environment interaction

项目摘要/摘要 颅缝融合症是一种颅面部疾病，其特征是颅缝过早融合。 缺陷间充质干细胞(MSCs)。严重颅缝早闭患者常有智力障碍 残疾(ID)。基因突变和环境因素都与颅缝早闭有关。 再加上MSC耗尽。我们建议确定基因与环境的相互作用机制。 通过研究颅缝早闭疾病基因Twist1和Tcf12如何与 环境风险因素，即母亲使用抗抑郁剂西酞普兰。重要的是，我们的目标是 建立基于MSC的治疗策略以减轻颅骨畸形和神经认知 颅缝融合功能障碍。这是创新和有意义的，因为我们对 颅缝融合症的环境因素和基因-环境相互作用及其新的治疗方法 毁灭性的混乱是迫切需要的。神经认知功能的研究在很大程度上被忽视了 颅突融合的动物模型，尽管认知异常，如ID经常 在颅缝融合症患者中观察到。颅缝融合症目前唯一的治疗选择是复杂的 手术，这是侵入性的，经常需要重新手术，因为颅骨再次融合。我们的MSC- 颅缝再生术创伤小，避免再融合，矫正颅骨畸形， 在临床上恢复升高的颅内压，并减少晚年的神经认知功能障碍 相关的Twist1/-小鼠颅缝融合模型。在Twist1/-小鼠和Twist1/-小鼠中都观察到Gli1 MSC耗竭 在那些母亲接触西酞普兰的人中。西酞普兰是一种选择性5-羟色胺再摄取抑制剂(SSRI)， 这是最常用的抗抑郁药物。母体SSRI的使用也称为 人类颅缝早闭的环境风险因素。这些结果导致假设Twist1 而Tcf12突变可能与西酞普兰相互作用，加剧颅骨和神经认知缺陷。 颅突融合，这将在目标1中进行测试。目标2将通过以下方式确定细胞和分子机制 哪些基因突变和母亲接触西酞普兰共同作用导致颅缝早闭。AIM 3将使用 我们最新开发的基于MSC的缝合再生方法来确定MSC是否以及如何再生 植入可缓解由基因突变引起的颅缝早闭患者的头骨和神经认知功能障碍， 西酞普兰以及它们之间的相互作用。总而言之，我们提议的研究建立在我们之前的发现基础上，并且 我们的发现将对提高对基因突变潜在机制的理解具有重要意义。 环境在颅骨融合症中的相互作用；它为改善儿童颅缝融合症的治疗提供了独特的机会 颅骨融合症。

PROJECT SUMMARY / ABSTRACT Craniosynostosis is a craniofacial disorder characterized by the premature fusion of cranial sutures with defective mesenchymal stem cells (MSCs). Patients with severe craniosynostosis often have intellectual disabilities (IDs). Both genetic mutations and environmental factors have been linked to craniosynostosis coupled with MSC depletion. We propose to determine gene-environment interaction mechanisms in craniosynostosis by addressing how craniosynostosis disease genes Twist1 and Tcf12 interplay with an environmental risk factor, namely maternal usage of the antidepressant citalopram. Importantly, we aim to establish a MSC-based therapeutic strategy to mitigate both skull dysmorphology and neurocognitive dysfunctions in craniosynostosis. This is innovative and significant because we have little understanding of environmental factors and gene-environment interactions in craniosynostosis, and new treatments for this devastating disorder are urgently needed. Neurocognitive functions have been largely neglected in studies of animal models of craniosynostosis, although cognitive abnormalities such as IDs have been frequently observed in craniosynostosis patients. The only current treatment option for craniosynostosis is complex surgery, which is invasive and often requires re-operation due to the calvarial bones fusing again. Our MSC- based cranial suture regeneration approach is less invasive, avoids re-fusion, corrects skull dysmorphology, restores elevated intracranial pressure, and reduces neurocognitive dysfunctions later in life in a clinically relevant Twist1+/- mouse model of craniosynostosis. Gli1+ MSC depletion is observed both in Twist1+/- mice and in those with maternal exposure to citalopram. Citalopram is a selective serotonin reuptake inhibitor (SSRI), which is the most commonly prescribed class of antidepressant drugs. Maternal SSRI usage is also known as an environmental risk factor for craniosynostosis in humans. These results lead to the hypothesis that Twist1 and Tcf12 mutations may interplay with citalopram in exacerbating skull and neurocognitive defects in craniosynostosis, which will be tested in Aim 1. Aim 2 will determine cellular and molecular mechanisms by which gene mutations and maternal citalopram exposure act together to cause craniosynostosis. Aim 3 will use our newly developed MSC-based suture regeneration approach to determine whether and how MSC implantation mitigates skull and neurocognitive dysfunctions in craniosynostosis caused by gene mutations, citalopram, and their interactions. Collectively, our proposed studies build upon our previous discoveries, and our findings will be highly significant for improving the understanding of mechanisms underlying gene- environment interplay in craniosynostosis; it offers a unique opportunity for improving treatment of infants with craniosynostosis.