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

BMP 信号在神经嵴细胞软骨形成命运决定中的作用

• 批准号: 8677591
• 负责人: Yoshihiro Komatsu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-14 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677591
• 关键词: ACVR1 gene; Achievement; Address; Applications Grants; Automobile Driving; Award; Biological Assay; Bone Morphogenetic Proteins; Bone Tissue; Cartilage; Cell Cycle; Cells; Chick Embryo; Chondrocytes; Chondrogenesis; Collagen; Congenital Abnormality; Cre-LoxP; Cyclin D1; Development; Developmental Biology; Disease; Doctor of Philosophy; Educational workshop; Elements; Embryo; Embryonic Development; Environment; Equipment and supply inventories; Ethics; Etiology; Face; Faculty; Gene Expression; Goals; Health; Healthcare; Human; Knowledge; Mandible; Meckel' s cartilage; Mediating; Mentors; Mentorship; Mesenchymal; Mesenchymal Stem Cells; Methods; Michigan; Molecular; Molecular Genetics; Mus; Neural Crest; Neural Crest Cell; Organ Culture Techniques; Osteoblasts; Pathogenesis; Pathway interactions; Patients; Phase; Plastics; Population; Positioning Attribute; Procedures; Production; Regulation; Reporter; Research; Role; School Dentistry; Scientific Advances and Accomplishments; Secure; Signal Pathway; Signal Transduction; Skeletal Development; Staging; System; Techniques; Testing; Tissue Engineering; Tissues; Training; Training and Education; United States National Institutes of Health; Universities; Work; aggrecan; base; bone; bone morphogenetic protein receptor type I; career; career development; cartilage development; craniofacial; design; embryonic stem cell; human embryonic stem cell; human embryonic stem cell line; in vivo; insight; loss of function; malformation; multipotent cell; novel; progenitor; programs; reconstruction; response; responsible research conduct; skeletal; skeletal abnormality; skeletal disorder; stem cell population; tissue regeneration; transcription factor

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.

项目摘要 这是NIH独立奖（K99/R00）的赠款提案，旨在促进 Yoshihiro Komatsu博士博士，密歇根大学牙科学院的研究员， 独立研究职位。候选人是一名受过训练的小鼠发育生物学家 颅面发育领域的研究和早期胚胎发生的研究记录 人类先天缺陷和先天性疾病的病因。他的目标是确保终身教师职位 并在颅面骨骼畸形和人类ES细胞领域建立自己的研究计划 基于软骨/骨组织再生。 在受到指导的（奖项中的K99阶段）期间，候选人将参加高级科学 讲习班，职业发展会议，道德培训和教育负责任的研究。他 将在大学的颅面发育生物学的丰富和协作环境中工作 密歇根州，牙科学院，在部门主席的指导下，保罗·克雷布斯巴赫博士，DDS，PhD， 以及Yuji Mishina博士博士和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的作用，以阐明软骨细胞命运 颅面发育过程中神经rest细胞的测定。同时，候选人将接受培训 针对人ES细胞的实验技术并制定其合理的研究策略。另外， 候选人将增加他对颅面发育的互补分析方法的清单 研究。这些成就将是通往独立（R00）阶段的基本桥梁。 在独立（本奖的R00阶段）期间，候选人将阐明BMP的作用 信号传导调节神经rest衍生的间充质祖细胞中的软骨细胞分化和 人ES衍生的间充质干细胞（MSC）。 R00期间拟议的研究之一将重点放在 通过ACVR1通过ACVR1在神经crest衍生中对软骨细胞的调节 颅面发育过程中的间充质祖细胞。我们希望发现如何 通过ACVR1过量的BMP信号导致颅面骨骼畸形。其他 R00期间的项目将重点介绍BMP信号通过ACVR1如何控制的分子机制 人ES衍生的MSC中的软骨细胞分化。我们预计会发现有关的新信息 BMP信号传导及其在有效产生人类ES细胞的软骨细胞中的实际作用。 这项研究具有重要的健康相关性，因为颅面骨骼畸形是 人类中最常见的疾病。此外，这项研究直接连接了紧急医疗保健 需要使用人ES细胞建立生成软骨细胞的策略，因为多个 每年有百万患者接受面部软骨重建相关的手术，这是一项昂贵的治疗方法。