Role of BMP signaling for chondrogenic fate determination in neural crest cells

项目总结 这是一项NIH独立之路奖(K99/R00)拨款提案，旨在促进 Yoshihiro Komatsu博士，密歇根大学牙科学院研究员 独立研究岗位。应聘者是一位训练有素的老鼠发育生物学家，具有显著的 颅面发育和早期胚胎发育领域的研究记录 人类出生缺陷和先天性疾病的病因学。他的目标是获得一个终身教职的职位。 并在头面部骨骼畸形和人类ES细胞领域建立了自己的研究计划- 以软骨/骨组织再生为基础。 在被指导期间(该奖项中的K99阶段)，候选人将参加高级科学 讲习班、职业发展会议、道德培训和负责任地开展研究的教育。他 将在加州大学颅面发育生物学丰富和协作的环境中工作 密歇根州口腔医学院，在系主任Paul Krebsbach博士的指导下，DDS，PhD， 以及共同导师Yuji Mishina博士和Vesa Kaartinen博士，博士。在K99阶段，候选人将 研究BMP信号通过BMP I型受体ACVR1在阐明软骨细胞命运中的作用 颅面发育过程中神经脊细胞的测定。与此同时，候选人将接受培训 人类胚胎干细胞的实验技术及其合理的研究策略。此外， 候选人将增加他的头面部发育补充分析方法的清单 学习。这些成就将是迈向独立(R00)阶段的根本桥梁。 在独立阶段(本奖项的R00阶段)，候选人将阐明BMP的角色 调节神经沟来源的间充质祖细胞和软骨细胞分化的信号 人ES来源的间充质干细胞(MSC)。R00期间的一项拟议研究将集中在 骨形态发生蛋白通过ACVR1信号对神经沟来源软骨细胞分化的调控 颅面发育过程中的间充质祖细胞。我们希望发现新的机制来说明 过多的BMP信号通过ACVR1导致头面部骨骼畸形。另一个 R00期间的项目将专注于BMP信号如何通过ACVR1调控 人胚胎干细胞向软骨细胞分化的研究。我们期待发现关于以下方面的新信息 骨形态发生蛋白信号转导及其在人胚胎干细胞高效生成软骨细胞中的作用。 这项研究具有重大的健康意义，因为颅面部骨骼畸形是 人类最常见的疾病。此外，这项研究直接联系到紧急医疗保健，即 需要建立使用人类ES细胞生成软骨细胞的策略，因为不止一个 每年有数百万患者接受与面部软骨重建相关的手术，这是一种昂贵的治疗方法。

PROJECT SUMMARY This is an NIH Pathway to independence Award (K99/R00) grant proposal, intended to promote the career of Dr. Yoshihiro Komatsu, PhD, a research fellow at the University of Michigan, School of Dentistry, into an independent research position. The Candidate is a trained mouse developmental biologist with a significant track record of research in the fields of craniofacial development and early embryogenesis for addressing the etiology of birth defects and congenital diseases in human. His goal is to secure a tenure-track faculty position and establish his own research program in the field of craniofacial skeletal malformations and human ES cell- based cartilage/bone tissue regeneration. During the mentored (K99 phase in this award), the Candidate will attend advanced scientific workshops, career development sessions, ethics training and education in responsible conduct of research. He will work within a rich and collaborative environment of Craniofacial Developmental Biology at University of Michigan, School of Dentistry, under the mentorship of the Department Chair, Dr. Paul Krebsbach, DDS, PhD, and co-mentors Dr. Yuji Mishina, PhD and Dr. Vesa Kaartinen, PhD. During the K99 phase, the Candidate will study the role of BMP signaling through BMP type I receptor, ACVR1, to elucidate chondrogenic cell fate determination in neural crest cells during craniofacial development. Meanwhile, the Candidate will be trained in the experimental techniques for human ES cells and developing its rational research strategies. In addition, the candidate will increase his inventory of complementary analysis methods for craniofacial developmental studies. These achievements will be the fundamental bridge to an independent (R00) phase. During the independent (R00 phase of this award), the Candidate will elucidate the role of BMP signaling that regulates chondrocyte differentiation in neural crest-derived mesenchymal progenitors and human ES-derived mesenchymal stem cells (MSC). One of the proposed studies during R00 will focus on the regulation of chondrocyte differentiation by BMP signaling through ACVR1 in neural crest-derived mesenchymal progenitors during craniofacial development. We expect to discover novel mechanisms for how an excess amount of BMP signaling through ACVR1 leads to craniofacial skeletal malformation. Another project during R00 will focus on the molecular mechanisms of how BMP signaling through ACVR1 governs the chondrocyte differentiation in human ES-derived MSC. We anticipate uncovering novel information regarding BMP signaling and its practical role in effectively generating chondrocytes from human ES cells. This research has major health relevance, because craniofacial skeletal malformations are one of the most frequent disorders in human. In addition, this research directly connects the urgent health care that is needed to establish the strategies of generating chondrocytes using human ES cells since more than one million patients undergo facial cartilage reconstruction-related procedures every year, a costly treatment.