microRNA tuning of neural crest osteogenesis

microRNA调节神经嵴成骨

基本信息

批准号：
9982300
负责人：
Nicole Isolde zur Nieden
金额：
$ 38.33万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982300
关键词：
Affect Aryl Hydrocarbon Receptor Bone Development Cartilage Cells Cephalic Congenital Abnormality Coupled Craniofacial Abnormalities DNA Binding Data Defect Development Diagnosis Diagnostic Disease Early Diagnosis Embryo Embryonic Development Engineering Environmental Protection Epigenetic Process Etiology Face Family Functional disorder Genetic Genetic Transcription Goals Human Human Development In Vitro Individual Knock-out Knowledge Lead Messenger RNA MicroRNAs Modeling Molecular Molecular Mechanisms of Action Morphology Mus National Institute of Dental and Craniofacial Research Neural Crest Neural Crest Cell Nuclear Organism Osteoblasts Osteogenesis Outcome Pathology Phenotype Play Populations at Risk Prevention Process Proteins Psychological Impact Public Domains Publishing Regulation Regulator Genes Reporting Repression Research Role Signal Transduction Skeleton Testing Time Tissues Transcriptional Activation Transgenic Organisms Xenopus base bone calcification craniofacial craniofacial bone craniofacial development craniofacial disorder developmental disease diagnostic biomarker epigenetic regulation experimental study genetic counselor human embryonic stem cell human pluripotent stem cell in vitro Model in vivo innovation malformation neuroregulation novel osteoblast differentiation osteogenic osteoprogenitor cell overexpression prevent promoter psychologic response skeletal skeletogenesis stem cell model trait transcription factor vertebrate embryos

Affect Aryl Hydrocarbon Receptor Bone Development Cartilage Cells Cephalic Congenital Abnormality Coupled Craniofacial Abnormalities DNA Binding Data Defect Development Diagnosis Diagnostic Disease Early Diagnosis Embryo Embryonic Development Engineering Environmental Protection Epigenetic Process Etiology Face Family Functional disorder Genetic Genetic Transcription Goals Human Human Development In Vitro Individual Knock-out Knowledge Lead Messenger RNA MicroRNAs Modeling Molecular Molecular Mechanisms of Action Morphology Mus National Institute of Dental and Craniofacial Research Neural Crest Neural Crest Cell Nuclear Organism Osteoblasts Osteogenesis Outcome Pathology Phenotype Play Populations at Risk Prevention Process Proteins Psychological Impact Public Domains Publishing Regulation Regulator Genes Reporting Repression Research Role Signal Transduction Skeleton Testing Time Tissues Transcriptional Activation Transgenic Organisms Xenopus base bone calcification craniofacial craniofacial bone craniofacial development craniofacial disorder developmental disease diagnostic biomarker epigenetic regulation experimental study genetic counselor human embryonic stem cell human pluripotent stem cell in vitro Model in vivo innovation malformation neuroregulation novel osteoblast differentiation osteogenic osteoprogenitor cell overexpression prevent promoter psychologic response skeletal skeletogenesis stem cell model trait transcription factor vertebrate embryos

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项目摘要

PROJECT SUMMARY Every 4 ½ minutes, a baby is born with a birth defect, including such that affect the craniofacial skeleton. These facial malformations cause disfigurement leading to long-term psychological impact and are often associated with physical dysfunction imposing tremendous burden on the affected individuals and their families. Although the causes for most of these severe developmental pathologies are still unknown, it is clear that the inappropriate formation and differentiation of neural crest (NC) cells, the cells that normally give rise to the osteoblasts in the affected craniofacial skeleton, plays a large part. Given the causality between miscontrolled osteoblast differentiation from the NC and the tissue malformations arising from it, an understanding of the molecular networks underlying NC development is crucial for the potential treatment or prevention of craniofacial defects, yet far from complete. For instance, the contribution of epigenetic regulators, such as microRNAs (miRNAs), to the formation of the craniofacial bones remains understudied, despite their potential as diagnostic markers. We study here the epigenetic regulation of NC development by a specific miRNA, miR361, which we have previously identified in our lab as being pro-osteogenic in an in vitro model of NC-osteogenesis. Characterizing the miR361 expression domain in mouse and Xenopus embryos coupled with the assessment of skeletal and NC phenotypes when miR361 is knocked out or overexpressed in these organisms will validate the function of miR361 during NC development in vivo. Assessing miR361's contribution to NC development using an innovative and effective in vitro NC differentiation model based on human pluripotent stem cells will show relevance for this microRNA in human development. Elaborating on the direct miR361 mRNA target and identifying NC-specific loci that are transcriptionally regulated downstream of miR361 will define the relationship between this miRNA, transcriptional activation in NC cells and their subsequent propensity for osteoblast differentiation. This knowledge is highly impactful as there is currently no information in the public domain that could explain the role of miR361 in bone development from the NC nor in any aspect of differentiation, development or disease. The results gained from this study will aid in the development of a more complete understanding of craniofacial osteogenesis that is inclusive of epigenetic regulators and promises to illuminate causes and treatments of developmental disorders of the craniofacial region in humans, which has a high priority in NIDCR's long-range plan.

项目摘要每4½分钟，一个婴儿天生就有出生缺陷，其中包括影响颅面骨骼的影响。这些面部畸形导致毁容导致长期心理影响，并且通常是与身体功能障碍有关，对受影响的个体及其家庭。尽管大多数这些严重发育性病变的原因仍然未知，但很明显神经rest（NC）细胞的不当形成和分化，通常会产生的细胞受影响的颅面骨骼中的成骨细胞起着很大的作用。考虑到之间的因果关系错误控制的成骨细胞与NC的分化以及由此产生的组织畸形，了解NC开发基础的分子网络对于潜在治疗或预防颅面缺陷，但远非完整。例如，表观遗传调节剂的贡献，例如microRNA（miRNA），颅面骨骼的形成仍然是理解的，作为诊断标记的潜力。我们在这里研究了特定miRNA对NC发育的表观遗传调节，MiR361我们已经具有先前在我们的实验室中鉴定为在NC稳定发生的体外模型中是促骨的。特征小鼠和爪蟾胚胎中的miR361表达结构域，并评估骨骼和当在这些生物中敲出或过表达miR361时，NC表型将验证 MiR361在体内发育期间。使用一种评估MiR361对NC开发的贡献基于人类多能干细胞的创新且有效的体外NC分化模型将显示与该microRNA有关人类发展的相关性。在直接miR361 mRNA靶标上详细说明识别MiR361下游的转录调节的NC特异性局部这种miRNA之间的关系，NC细胞中的转录激活与他们随后对成骨细胞分化。这些知识具有很高的影响力，因为目前尚无公众信息可以解释MiR361在NC发育中的作用的领域分化，发育或疾病。从这项研究中获得的结果将有助于发展对包括表观遗传调节剂的颅面成骨的更全面了解有望阐明人类颅面地区发育障碍的原因和治疗在NIDCR的远程计划中有很高的优先事项。