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A Hippo-Yap Pathway in Cranial Bone Development and Regeneration

颅骨发育和再生中的河马-雅普通路

基本信息

批准号：
10192701
负责人：
Jun Wang
金额：
$ 14.79万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192701
关键词：
Alleles Binding Sites Bioinformatics Bone Density Bone Development Bone Injury Bone Regeneration CRISPR/Cas technology Calvaria Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cell Nucleus Cell Proliferation Cells Cephalic Cre driver DNA Binding Data Defect Embryo Environment Extracellular Matrix Future Gene Expression Genes Goals Hydrogels In Vitro Joint structure of suture of skull Ligands Mandible Mechanics Mediating Mediator of activation protein Mentored Research Scientist Development Award Methods Modeling Mus NOTCH3 gene Natural regeneration Neural Crest Nuclear Nucleic Acid Regulatory Sequences Organ Size Osteoblasts Osteogenesis Pathway interactions Phosphotransferases Physiologic Ossification Play Regenerative Medicine Regulator Genes Reporting Research Role Sampling Signal Pathway Signal Transduction Survivors System Testing Time Tissues Training bone conditional knockout craniofacial craniofacial development extracellular genome editing in vitro activity in vivo inhibitor/antagonist knock-down mechanical properties mouse model mutant notch protein novel osteoblast differentiation osteoblast proliferation postnatal receptor repaired response severe injury skeletal tool transcriptome sequencing

项目摘要

The role of the Hippo-signaling pathway, an evolutionarily conserved organ size control pathway, in cranial bone development and regeneration is poorly understood. We specifically inactivated the Hippo component Salv, and Hippo downstream effectors Yap and Taz in the cranial neural crest (CNC) using the Wnt1cre driver and Wnt1cre2SOR drivers. Salv conditional knock-out (CKO) mutants had dramatically enlarged calvarial bones and cranial sutures with increased calvarial bone density, whereas mutants of Taz homozygous and Yap heterozygous CKO had a range of survival times from E14.5 to postnatal 8 weeks with a range of calvarial bone defects with Wormian bones and decreased calvarial bone density. Notably, our preliminary data suggested that expression and subcellular localization of Yap changes upon Hippo kinase activity, extracellular matrix rigidity and Notch signaling activity. In this proposed K01 study, we investigate the function of Hippo signaling and Yap/Taz mediated signaling crosstalk during cranial bone development and regeneration and will study three aims: 1) To investigate the hypothesis that Hippo signaling and extracellular environment cooperatively regulate osteoblast proliferation and differentiation during cranial bone formation; 2) To investigate the signaling cross talk between Hippo and Notch signaling during cranial bone development; 3) To identify novel target genes of Hippo signaling during cranial bone development and regeneration. My research will focus on bone regeneration and treatment of severely injured bone. This K01 study will provide preliminary data and potential targets in bone regenerative medicine for my subsequent R01 application.

河马信号通路的作用，一种进化上保守的器官大小控制在颅骨发育和再生过程中，人们对此知之甚少。我们特别指出停用河马组件Salv以及河马下游效应器Yap和Taz 使用Wnt1cre驱动程序和Wnt1cre2SOR驱动程序的脑神经脊线(CNC)。SAIV条件性基因敲除(CKO)突变体的颅骨和颅缝显著增大增加颅骨骨密度，而Taz纯合子和YAP杂合子突变 CKO的存活时间从胚胎14.5周到出生后8周，有一系列的头盖骨骨缺损伴蠕虫骨，颅骨骨密度降低。值得注意的是，我们的初步数据表明，YAP的表达和亚细胞定位在河马蛋白激酶活性、细胞外基质刚性和Notch信号活性。在这项建议的K01研究中，我们研究了河马信号和YAP/Taz的功能颅骨发育和再生过程中的信号串扰研究的三个目的：1)研究河马信号和细胞外信号的假说颅骨发育中环境对成骨细胞增殖分化的协同调节 2)研究河马和Notch信号之间的信号串扰 3)寻找河马信号转导新的靶基因。颅骨发育和再生。我的研究将集中在骨再生和严重损伤骨的治疗上。这 K01研究将为骨再生医学提供初步数据和潜在靶点我随后的R01应用程序。