Mechanisms and rescue of craniosynostosis associated with gene-environment interaction

基因-环境相互作用相关颅缝早闭的机制及抢救

基本信息

批准号：
10275469
负责人：
Yang Chai
金额：
$ 62.7万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10275469
关键词：
Address Affect Animal Model Antidepressive Agents Behavior Behavioral Brain Calvaria Cell Therapy Cells Citalopram Cognitive Complex Congenital Abnormality Congenital Disorders Coupled Craniofacial Abnormalities Craniosynostosis DNA Sequence Alteration Defect Deformity Depressed mood Disease Dura Mater Dysmorphology Environment Environmental Risk Factor Exposure to Functional disorder Gene Mutation Genes Goals Hormones Human Impairment Implant Individual Infant Intellectual functioning disability Intracranial Hypertension Intracranial Pressure Joint structure of suture of skull Knowledge Lead Life Link Maternal Exposure Mediating Meninges Mental Depression Mesenchymal Stem Cells Modeling Molecular Morphology Mus Mutant Strains Mice Mutation Natural regeneration Neurocognitive Neurocognitive Deficit Neurologic Neurotransmitters Operative Surgical Procedures Patients Penetration Pharmaceutical Preparations Phenotype Quality of life Selective Serotonin Reuptake Inhibitor Serotonin Severities Structure Surgical sutures TWIST1 gene Testing Therapeutic Therapeutic Studies United States WNT Signaling Pathway Woman base bone brain volume clinically relevant craniofacial disorder cranium fighting gene environment interaction implantation improved in utero innovation mouse model neglect operation pregnant premature prenatal exposure recruit restoration scaffold skull base stem cells tissue regeneration transcription factor

项目摘要

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.

项目概要/摘要颅缝早闭是一种颅面疾病，其特征是颅缝与颅骨过早融合有缺陷的间充质干细胞（MSC）。严重颅缝早闭的患者往往智力低下残疾（ID）。基因突变和环境因素都与颅缝早闭有关加上 MSC 耗竭。我们建议确定基因与环境的相互作用机制通过解决颅缝早闭疾病基因 Twist1 和 Tcf12 如何与颅缝早闭相互作用环境风险因素，即母亲使用抗抑郁药西酞普兰。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功能颅缝早闭功能障碍。这是创新且意义重大的，因为我们对颅缝早闭的环境因素和基因-环境相互作用及其新疗法迫切需要毁灭性的混乱。神经认知功能在研究中很大程度上被忽视了颅缝早闭的动物模型，尽管诸如 ID 之类的认知异常经常被在颅缝早闭患者中观察到。目前颅缝早闭唯一的治疗选择很复杂手术是一种侵入性手术，由于颅骨再次融合，通常需要再次手术。我们的 MSC- 基于颅缝再生的方法侵入性较小，避免再融合，纠正颅骨畸形，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+/- 小鼠颅缝早闭模型。在 Twist1+/- 小鼠和母亲接触西酞普兰的患者。西酞普兰是一种选择性血清素再摄取抑制剂（SSRI），这是最常用的一类抗抑郁药物。母亲使用 SSRI 也称为人类颅缝早闭的环境危险因素。这些结果得出这样的假设：Twist1 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缝早闭，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西酞普兰暴露共同作用导致颅缝早闭。目标 3 将使用我们新开发的基于 MSC 的缝线再生方法可确定 MSC 是否以及如何再生植入减轻了基因突变引起的颅缝早闭的颅骨和神经认知功能障碍，西酞普兰及其相互作用。总的来说，我们提出的研究建立在我们之前的发现的基础上，并且我们的研究结果对于增进对基因潜在机制的理解具有非常重要的意义颅缝早闭中环境的相互作用；它为改善婴儿的治疗提供了独特的机会颅缝早闭。