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Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

BMP信号增强引起的颅缝早闭的分子发病机制

基本信息

批准号：
9902971
负责人：
Yuji MISHINA
金额：
$ 21.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-07 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902971
关键词：
Address Administrative Supplement Affect Agonist Anterior Apoptosis BMPR1A gene Bone Diseases Bone Morphogenetic Proteins Branchial arch structure Cartilage Cell Death Cell Differentiation process Cell Line Cells Cephalic Chondrocytes Chondrogenesis Chronic Headaches Clinical Collaborations Congenital Abnormality Craniosynostosis Data Defect Deformity Development Developmental Process Disease Dose Early identification Embryo Event FRAP1 gene Fibroblast Growth Factor Genetic Goals Growth Factor Human Impaired cognition Infant Intracranial Hypertension Investigation Joint structure of suture of skull Lead Live Birth Measurement Measures Mesenchyme Michigan Modeling Molecular Molecular Target Mus Neural Crest Neural Crest Cell Normal Cell Oligonucleotides Organoids Osteogenesis Parents Pathogenesis Pathologic Pathway interactions Pattern Pharmacology Phenotype Phosphotransferases Play Population Population Control Prevalence Prevention Receptor Gene Reconstructive Surgical Procedures Rodent Model Role Shapes Signal Pathway Signal Transduction Signaling Protein Site Skeletal system Smad Proteins Stem cells Surgical sutures Syndrome TP53 gene Therapeutic Transgenic Mice Universities Up-Regulation base bone morphogenetic protein receptors causal variant cell fate specification clinical phenotype craniofacial cranium gain of function mutation insight medical schools molecular targeted therapies mouse model multipotent cell mutant parent grant premature receptor skull abnormality stem cell biology stem cell population suture fusion

项目摘要

ABSTRACT Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion resulting in abnormal skull shape. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the skeletal system. The only treatment is extensive, and often multiple, reconstructive surgeries. The long-term goal of the parent R01 is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis in the rodent models. We have established a conditional mouse model, which shows enhanced neural crest-specific BMP signaling via BMP type 1 receptor BMPR1A in the skull and sutures. This model is unique and important due to: 1) upregulation of p53-induced apoptosis is observed, and 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, suggesting that craniosynostosis is not a bone disease but stem cell disease. Our recent data strongly suggest that augmented BMP-Smad signaling activities influences cell fate specification of multi-potent neural crest precursors towards chondrogenic lineage through mTOR signaling and Wnt canonical signaling activities. In this Administrative Supplements, we propose a new collaboration with Dr. Jason Spence at the University of Michigan Medical School to directly address cellular and molecular mechanisms of how increased BMP signaling alters cell-fate specification in cranial neural crest cells. We will use single cell derived sphere formation and 3-dimentional organoid formation in culture to directly measure multi-potency of primary neural crest cells from early stage embryos as well as established stem cell lines from neural crests. Results from this collaboration will therefore provide better insights for molecular targets to restore normal cell fate determination ability and thus potential therapeutic treatment of human cases.

摘要

项目成果

期刊论文数量（49）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biocompatible Polymeric Analogues of DMSO Prepared by Atom Transfer Radical Polymerization.

DOI：
10.1021/acs.biomac.6b01553
发表时间：
2017-02-13
期刊：
Biomacromolecules
影响因子：
6.2
作者：
Li S;Chung HS;Simakova A;Wang Z;Park S;Fu L;Cohen-Karni D;Averick S;Matyjaszewski K
通讯作者：
Matyjaszewski K

Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury.

DOI：
10.1038/srep32514
发表时间：
2016-09-12
期刊：
Scientific reports
影响因子：
4.6
作者：
Agarwal S;Loder S;Cholok D;Peterson J;Li J;Fireman D;Breuler C;Hsieh HS;Ranganathan K;Hwang C;Drake J;Li S;Chan CK;Longaker MT;Levi B
通讯作者：
Levi B

Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition.

通过 ACVR1 和 BMPR1A 的骨形态发生蛋白信号传导负向调节骨量以及骨成分的改变

DOI：
10.1016/j.jsb.2017.11.010
发表时间：
2018-03
期刊：
Journal of structural biology
影响因子：
3
作者：
Shi C;Mandair GS;Zhang H;Vanrenterghem GG;Ridella R;Takahashi A;Zhang Y;Kohn DH;Morris MD;Mishina Y;Sun H
通讯作者：
Sun H

Tissue Preparation and Immunostaining of Mouse Craniofacial Tissues and Undecalcified Bone.

DOI：
10.3791/59113
发表时间：
2019-05
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Jingwen Yang;Haichun Pan;Y. Mishina
通讯作者：
Jingwen Yang;Haichun Pan;Y. Mishina

Cationic Hyperbranched Polymers with Biocompatible Shells for siRNA Delivery.

阳离子超支聚合物，具有生物相容性壳，用于siRNA递送。

DOI：
10.1021/acs.biomac.8b00902
发表时间：
2018-09-10
期刊：
Biomacromolecules
影响因子：
6.2
作者：
Li S;Omi M;Cartieri F;Konkolewicz D;Mao G;Gao H;Averick SE;Mishina Y;Matyjaszewski K
通讯作者：
Matyjaszewski K