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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：
9926053
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/9926053
关键词：
Alleles Binding Sites Bioinformatics Bone Density Bone Development Bone Regeneration CRISPR/Cas technology Calvaria Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cell Nucleus Cell Proliferation Cells Cephalic DNA Binding Data Defect Embryo Environment Extracellular Matrix Future Gene Expression Genes Goals Hydrogels In Vitro Joint structure of suture of skull Knock-out 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 craniofacial craniofacial development extracellular genome editing in vitro activity in vivo inhibitor/antagonist injured knock-down mechanical properties mouse model mutant notch protein novel postnatal receptor repaired response 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.

海马信号通路的作用，一种进化上保守的器官大小控制在颅骨发育和再生的途径是知之甚少。我们特别使Hippo组分Salv和Hippo下游效应物雅普和Taz失活，使用Wnt 1cre驱动器和Wnt 1cre 2SOR驱动器的颅神经嵴（CNC）。条件Salv CKO基因敲除突变体的颅骨和颅缝显著增大，增加颅骨骨密度，而Taz纯合子和雅普杂合子的突变体 CKO的存活时间从E14.5到出生后8周不等，蠕虫状骨的骨缺损和颅骨骨密度降低。值得注意的是，我们的初步的数据表明，雅普的表达和亚细胞定位的变化， Hippo激酶活性、细胞外基质刚性和Notch信号传导活性。在这项K 01研究中，我们研究了Hippo信号转导和雅普/Taz的功能，介导的信号串扰在颅骨发育和再生，本研究的目的有三：1）探讨Hippo信号通路与细胞外信号通路之间的关系，颅外环境协同调控成骨细胞增殖和分化 2）研究Hippo和Notch信号之间的信号串扰 3）为了鉴定Hippo信号转导的新靶基因，颅骨发育和再生。我的研究将集中在骨再生和治疗严重受伤的骨。这 K 01研究将为骨再生医学提供初步数据和潜在靶点，我的R 01申请