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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：
10434153
负责人：
Yang Chai
金额：
$ 60.74万
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/10434153
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 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 dysfunction 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.

项目摘要/摘要