In utero rescue of cleft palate using maternal administration of folic acid

使用叶酸在子宫内挽救腭裂

基本信息

批准号：
10646021
负责人：
Irfan Saadi
金额：
$ 23.25万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646021
关键词：
Actins Actomyosin Affect Alleles Binding Birth Cell Proliferation Cells Cleft Palate Coiled-Coil Domain Complex Congenital Abnormality Craniofacial Abnormalities Cytoskeleton Data Defect Development Dose Early Intervention Embryo Environment Environmental Risk Factor Etiology F-Actin Female Folic Acid Future Genetic Goals Growth Hour Human Incidence Intake Intervention Intervention Studies Intraperitoneal Injections Knock-in Knowledge Mediating Mesenchyme Methodology Methods Microtubules Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Myosin Type II Neural Tube Closure Neural Tube Defects Palate Patients Phenotype Process Proteomics Scaffolding Protein Smoking Source Specific qualifier value Stains Syndrome System Therapeutic Three-dimensional analysis Time Tissues cell growth regulation cleft lip and palate dietary dosage experimental study folic acid supplementation improved in utero innovation insight intraperitoneal mouse model mutant non-muscle myosin novel orofacial cleft palatal shelves palatogenesis phosphoproteomics pregnant prevent translational potential

Actins Actomyosin Affect Alleles Binding Birth Cell Proliferation Cells Cleft Palate Coiled-Coil Domain Complex Congenital Abnormality Craniofacial Abnormalities Cytoskeleton Data Defect Development Dose Early Intervention Embryo Environment Environmental Risk Factor Etiology F-Actin Female Folic Acid Future Genetic Goals Growth Hour Human Incidence Intake Intervention Intervention Studies Intraperitoneal Injections Knock-in Knowledge Mediating Mesenchyme Methodology Methods Microtubules Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Myosin Type II Neural Tube Closure Neural Tube Defects Palate Patients Phenotype Process Proteomics Scaffolding Protein Smoking Source Specific qualifier value Stains Syndrome System Therapeutic Three-dimensional analysis Time Tissues cell growth regulation cleft lip and palate dietary dosage experimental study folic acid supplementation improved in utero innovation insight intraperitoneal mouse model mutant non-muscle myosin novel orofacial cleft palatal shelves palatogenesis phosphoproteomics pregnant prevent translational potential

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项目摘要

PROJECT SUMMARY Craniofacial anomalies accompany a third of all birth defects, with isolated or nonsyndromic clefts of the lip and palate (CL/P) alone occurring in 1/700 births worldwide. These isolated CL/P have a complex etiology including both genetic and environmental factors. Isolated cleft palate (CP) alone accounts for 1/1700 cases in the US. In addition, there are >400 syndromes with CP as a phenotype. Environmental factors such as folate intake and smoking have been shown to affect maternal environment. While dietary maternal folic acid supplementation has consistently shown ameliorative effects on neural tube defects, its effect on reducing the occurrence of CL/P has been variable both in human and in mouse models. Sources of this variability include the dosage and delivery of folic acid as well as ability to assess the impact of the treatment in mouse models. Several human studies have speculated that low folic acid dose is not sufficient to prevent CL/P, and that higher doses are more effective. Our preliminary data indicate that a high daily dose of folic acid given intraperitoneally to pregnant mice in two short developmental windows is sufficient to rescue CP in utero in Specc1l mouse model of CP. Specc1l deficiency leads to actin cytoskeletal defects, which results in palatal shelf elevation delay. We have developed several quantitative 2-D and 3-D analyses to characterize the timing and cellular changes that occur during palatal shelf growth and elevation. We posit that in utero folic acid supplementation has an ameliorative effect on the dynamics of palate closure. In contrast to neural tube defects, we argue that rescue of CP requires a higher daily dose of folic acid administered intraperitoneally but for a short window of time. To our knowledge, we are the first to use intraperitoneal injection of folic acid to rescue CP. Folic acid has been used extensively in human studies and has been safe even at relatively high doses. The objective of this proposal is to determine the minimum possible dose and treatment window for an effective rescue of CP and to study which aspects of palate closure dynamics are impacted by folic acid supplementation. We will also use sophisticated proteomic and phosphoproteomic analysis of palatal shelf tissue to determine the molecular consequence of folic acid treatment. Together, these studies will establish the experimental system and methods to study maternal folic acid rescue of CP in mice that can be applied to other mouse models. Importantly, these studies will lead to future therapeutic strategies to reduce the incidence of CL/P in humans.

项目摘要颅面异常伴随着所有先天缺陷的三分之一，嘴唇的孤立或非龙骨裂缝味觉（Cl/p）仅发生在全球1/700个出生中。这些孤立的cl/p具有复杂的病因，包括遗传和环境因素。在美国，仅隔离的裂口（CP）占1/1700案件。在此外，有> 400个CP作为表型的综合症。环境因素，例如叶酸摄入和吸烟已被证明会影响孕产妇环境。而饮食母体叶酸补充剂始终显示出对神经管缺陷的改善作用，其对减少CL/P的影响在人类和小鼠模型中都是可变的。这种可变性的来源包括剂量和递送叶酸以及评估治疗在小鼠模型中的影响的能力。一些人类研究已经推测低叶酸剂量不足以防止Cl/p，并且更高的剂量更多有效的。我们的初步数据表明，腹膜内的每日剂量高剂量在两个简短的发育窗口中，足以在CP的SpecC1L鼠标模型中挽救子宫内的CP。 SPECC1L 缺乏会导致肌动蛋白细胞骨架缺陷，从而导致pale质货架升高延迟。我们已经发展了几种定量的2-D和3-D分析，以表征在此期间发生的时间和细胞变化帕拉特架子的生长和高程。我们认为，在子宫叶酸中补充有改善作用关于口感闭合的动力。与神经管缺陷相反，我们认为CP的营救需要较高的每日剂量叶酸腹膜内施用，但时间很短。据我们所知，我们是第一个使用腹膜内注射叶酸来挽救CP的人。叶酸已广泛使用人类研究，即使在相对较高的剂量下也是安全的。该提议的目的是确定有效营救CP的最低剂量和治疗窗口，并研究了哪些方面口感闭合动力学受到补充叶酸的影响。我们还将使用复杂的蛋白质组学和对pa架组织的磷酸化蛋白质组学分析，以确定叶酸的分子结果治疗。这些研究将共同建立研究孕产妇的实验系统和方法可以应用于其他小鼠模型的小鼠中CP的酸营救。重要的是，这些研究将导致未来减少人类Cl/p发病率的未来治疗策略。