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: 7952410
• 负责人: Yoshihiro Komatsu
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952410
• 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; 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; public health relevance; reconstruction; response; responsible research conduct; skeletal; skeletal abnormality; skeletal disorder; stem cell population; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposed project is designed to elucidate the function of BMP signaling for chondrogenic cell fate determination in neural crest cells. Our study will yield novel and critical insights into the molecular pathogenesis of craniofacial skeletal abnormalities in humans, and will also provide novel techniques for the controlled differentiation of functional chondrocytes from human ES cells for tissue engineering applications.

描述（由申请人提供）：这是NIH独立奖（K99/R00）的赠款提案，旨在促进密歇根大学牙科学院研究员Yoshihiro Komatsu博士的职业，成为独立的研究职位。该候选人是一名受过训练的小鼠发育生物学家，在颅面发育领域和早期胚胎发生方面具有重大的研究记录，以解决人类先天缺陷和先天性疾病的病因。他的目标是确保终身训练的教师职位，并在颅面骨骼畸形和人类ES细胞软骨/骨组织再生领域建立自己的研究计划。 在指导的（本奖项中的K99阶段）期间，候选人将参加高级科学研讨会，职业发展会议，道德培训和负责任的研究的教育。他将在密歇根大学，牙科学院的颅面发育生物学的丰富和协作环境中工作，在部门主席的指导下，保罗·克雷布斯巴赫博士，DDS，博士学位，博士和尤吉·米希纳（Yuji Mishina）博士，博士学位和维萨·卡蒂宁（Vesa Kaartinen）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，以阐明在颅面发育过程中神经CREST细胞中的软骨细胞命运测定。同时，候选人将接受针对人类ES细胞的实验技术并制定其理性研究策略的培训。此外，候选人将增加其用于颅面发育研究的互补分析方法的清单。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信号传导的作用，该信号在神经衍生的间充质祖细胞和人ES衍生的间充质干细胞（MSC）中调节软骨细胞分化（MSC）。 R00期间提出的一项研究将重点介绍BMP信号通过ACVR1通过ACVR1在颅面发育过程中通过ACVR1通过ACVR1进行调节。我们期望发现通过ACVR1过量信号传导导致颅面骨骼畸形的新机制。 R00期间的另一个项目将重点介绍BMP信号通过ACVR1如何控制人ES衍生MSC中软骨细胞分化的分子机制。我们预计会发现有关BMP信号传导及其在有效产生人类ES细胞软骨细胞中的实际作用的新信息。 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最常见的疾病之一。此外，这项研究直接连接了需要使用人ES细胞建立软骨细胞产生软骨细胞的策略所需的紧急医疗保健，因为每年有超过一百万的患者接受面部软骨重建相关程序，这是一种昂贵的治疗。 公共卫生相关性：该提出的项目旨在阐明BMP信号传导在神经rest细胞中确定软骨细胞命运的功能。我们的研究将对人类颅面骨骼异常的分子发病机理产生新的和批判性的见解，并且还将为人类ES细胞的功能性软骨细胞的控制性分化提供新技术，以用于组织工程应用。