Role of Irf6 in palatal epithelium

Irf6 在腭上皮中的作用

基本信息

批准号：
8450332
负责人：
Youssef A Kousa
金额：
$ 2.65万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-16 至 2014-02-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450332
关键词：
Accounting Adenovirus Vector Adhesions Affect Alleles Amniotic Fluid Animal Model Asians Biological Biological Assay Birth Blood Circulation Breathing Cardiovascular system Categories Caucasians Caucasoid Race Cell physiology Cells Child Cleaved cell Cleft Lip Cleft Palate Clinical Congenital Abnormality Connective Tissue Data Defect Development Diagnosis Disease Dose Eating Embryo Engineering Ensure Epidermis Epithelial Cells Epithelium Excision Functional disorder Gene Delivery Genes Genetic Goals Health Human Human Genetics In Vitro Individual Interferons Intervention Knockout Mice Laboratories Lead Life Medial Mediating Mediator of activation protein Medical Mesenchymal Minor Molecular Morbidity - disease rate Mus Musculoskeletal Mutation Nasal cavity National Institute of Dental and Craniofacial Research Neonatal Neurologic Oral Oral Pathology Oral cavity Palate Pathogenesis Patients Periderm Phenotype Prevalence Prevention strategy Process Protocols documentation Risk Role Severities Site Teflon Therapeutic Intervention Time Tissues Tropism United States Van der Woude syndrome Weight Work base body system cancer risk cell type cleft lip and palate clinically significant craniofacial design drinking feeding in utero in vivo interest keratinocyte life time cost mortality mouse model novel palatal shelves palatogenesis postnatal prevent promoter research study therapy design

项目摘要

DESCRIPTION (provided by applicant): The palate separates the oral and nasal cavity and allows breathing to occur alongside eating and drinking. Two broad categories of cell types are critical during palatal development; an epithelial cell layer that covers the palatal shelves and mesenchymal cells that become connective tissue, ultimately providing support and integrity. In humans and mice, dysfunction of either of these cell layers leads to clefting, a common developmental defect with serious postnatal consequences. A cleft can lead to feeding difficulty and the inability to gain or maintain weight at critical neonatal periods. Our group identified Interferon Regulatory Factor 6 (IRF6) as a major cause of clefting in humans. We are interested in identifying the mechanisms of clefting due to mutations in IRF6 and in designing interventions to prevent this birth defect. To realize this goal, our lab developed a mouse model. Thus far, our studies uncovered several important facts about Irf6 and its role in palatal development. First, we know that Irf6 is an essential regulator of proliferation and differentiation in keratinocytes, type of epithelial cell. Second, we demonstrated that Irf6 is expressed most robustly during palatal development in the periderm and Medial Edge Epithelium (MEE), epithelial cells that are critical for palatal formation. Third, we know that changes in Irf6 dose lead to clefting and oral adhesions in the mouse. Finally, we engineered laboratory protocols and mouse models to manipulate the concentration of Irf6 in palatal epithelial cells. Based on these facts, I hypothesize that changes in Irf6 dose in the periderm and MEE will affect palatal development. In Aim I, my goal is to reduce Irf6 dose in the MEE cells of otherwise normal mice and analyze the changes in palatal development that ensue. Based on previous data and preliminary findings, I predict that palatal development will not conclude due to the importance of the MEE and Irf6 in the process. In Aim II, my goal is to deliver Irf6 using an Adenoviral vehicle to periderm cells of Irf6-deficient embryos. In these experiments, I predict that Irf6 delivery to the periderm will rescue cellular function, leading to a significant decrease in oral cavity adhesions. This work has technical, biological and clinical significance. Technically, I have proposed a gene delivery protocol to the oral cavity, something that can be useful to other oral pathologies and genes. We have also created an Irf6 conditional allele, which can be used to assay the function of Irf6 in other tissues and at different timepoints. Biologically, we have proposed highly sophisticated gene manipulation protocols for the periderm and the MEE to examine their specific utility in palatal development as a function of Irf6. Clinically, Aim II provides proof-of principal experiments in mitigating the severity or preventing cleft formation during embryologic development.

描述（由申请人提供）：口感将口腔和鼻腔分开，允许呼吸与饮食一起发生。两种广泛的细胞类型至关重要。覆盖帕拉特架子和间充质细胞的上皮细胞层，这些细胞成为结缔组织，最终提供支持和完整性。在人类和小鼠中，这两个细胞层的功能障碍都导致裂纹，这是一种常见的发育缺陷，产后严重。裂缝会导致进食困难，并且无法在关键的新生儿时期增加或保持体重。我们的小组将干扰素调节因子6（IRF6）确定为人类裂变的主要原因。我们有兴趣确定由于IRF6突变引起的裂缘机制以及设计干预措施以防止这种出生缺陷。为了实现这一目标，我们的实验室开发了鼠标模型。到目前为止，我们的研究发现了有关IRF6及其在palatal发育中的作用的几个重要事实。首先，我们知道IRF6是角质形成细胞增殖和分化的必不可少的调节剂，类型的上皮细胞。其次，我们证明了IRF6在palatal发育过程中最强大的表达，在Periderm和内侧边缘上皮（MEE），这是对pa骨形成至关重要的上皮细胞。第三，我们知道IRF6剂量的变化会导致小鼠的口服和口服粘连。最后，我们设计了实验室方案和小鼠模型，以操纵palatal上皮细胞中IRF6的浓度。基于这些事实，我假设Periderm和MEE中IRF6剂量的变化会影响帕拉塔尔的发展。在AIM I中，我的目标是减少正常小鼠的MEE细胞中的IRF6剂量，并分析随后发生的palatal发育变化。根据先前的数据和初步发现，我预测，由于MEE和IRF6在此过程中的重要性，帕拉塔尔的发展不会得出结论。在AIM II中，我的目标是使用腺病毒载体运送IRF6到IRF6缺陷胚胎的细胞。在这些实验中，我预测IRF6向 Periderm将挽救细胞功能，从而导致口腔粘连显着降低。这项工作具有技术，生物学和临床意义。从技术上讲，我已经向口腔提出了一种基因递送方案，这对其他口腔病理和基因可能有用。我们还创建了一个IRF6条件等位基因，该等位基因可用于在其他组织和不同时间点分析IRF6的功能。从生物学上讲，我们提出了针对Periderm和MEE的高度复杂的基因操纵方案，以检查其在pa骨发育中的特定效用，这是IRF6的函数。临床上，AIM II提供证明在减轻胚胎学过程中缓解严重程度或防止裂口形成的主要实验。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development.

DOI：
10.1038/s41598-017-06310-z
发表时间：
2017-08-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Fakhouri WD;Metwalli K;Naji A;Bakhiet S;Quispe-Salcedo A;Nitschke L;Kousa YA;Schutte BC
通讯作者：
Schutte BC