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独立之路奖(K99/R00)拨款提案，旨在促进密歇根大学牙科学院研究员小松义弘博士的职业生涯进入独立研究职位。应聘者是一名训练有素的小鼠发育生物学家，在研究人类出生缺陷和先天性疾病的出生缺陷和早期胚胎发生领域有着丰富的研究记录。他的目标是获得终身教职，并在颅面骨骼畸形和基于人类ES细胞的软骨/骨组织再生领域建立自己的研究计划。在被指导期间(该奖项中的K99阶段)，候选人将参加高级科学研讨会、职业发展会议、道德培训和负责任地进行研究的教育。他将在密歇根大学牙科学院颅面发育生物学丰富而合作的环境中工作，在系主任保罗·克雷布斯巴赫博士、DDS博士、博士导师以及共同导师Yuji Mishina博士和Vesa Kaartinen博士博士的指导下工作。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脊细胞中软骨细胞命运的决定。同时，候选人将接受人类ES细胞实验技术方面的培训，并制定其合理的研究策略。此外，候选人将增加他的补充分析方法的清单，用于颅面发育研究。这些成就将是迈向独立(R00)阶段的根本桥梁。在独立阶段(该奖项的R00阶段)，候选人将阐明BMP信号在神经脊来源的间充质干细胞和人类胚胎来源的间充质干细胞(MSC)中调节软骨细胞分化的作用。R00期间的一项拟议研究将侧重于在颅面发育过程中，通过ACVR1通过BMP信号调节神经沟来源的间充质祖细胞对软骨细胞分化的调控。我们期望发现通过ACVR1过量的BMP信号如何导致头面部骨骼畸形的新机制。R00期间的另一个项目将专注于BMP信号如何通过ACVR1调控人ES来源的MSC软骨细胞分化的分子机制。我们期待着揭示关于BMP信号的新信息及其在有效地从人类ES细胞中产生软骨细胞中的实际作用。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之一。此外，这项研究直接联系到建立使用人类ES细胞生成软骨细胞的策略所需的紧急医疗保健，因为每年有100多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。 公共卫生相关性：这项拟议的项目旨在阐明BMP信号在神经脊细胞中决定软骨细胞命运的功能。我们的研究将为人类颅面部骨骼异常的分子发病机制提供新的和关键的见解，并将为组织工程应用提供从人类ES细胞控制分化功能软骨细胞的新技术。