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: 8100291
• 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 2012-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100291
• 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 Yoshihiro Komatsu 博士的职业生涯进入独立研究职位。该候选人是一位训练有素的小鼠发育生物学家，在颅面发育和早期胚胎发生领域具有重要的研究记录，以解决人类出生缺陷和先天性疾病的病因学。他的目标是获得终身教授职位，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项目。 在指导期间（该奖项的 K99 阶段），候选人将参加高级科学研讨会、职业发展课程、道德培训和负责任的研究行为教育。他将在密歇根大学牙科学院颅面发育生物学丰富的协作环境中工作，在系主任 Paul Krebsbach 博士（DDS）和共同导师 Yuji Mishina 博士和 Vesa Kaartinen 博士的指导下工作。在 K99 阶段，候选人将通过 BMP I 型受体 ACVR1 研究 BMP 信号传导的作用，以阐明颅面发育过程中神经嵴细胞中软骨形成细胞命运的决定。同时，候选人将接受人类胚胎干细胞实验技术的培训，并制定合理的研究策略。此外，候选人将增加颅面发育研究的补充分析方法的库存。这些成就将成为通往独立（R00）阶段的基础桥梁。 在独立（该奖项的 R00 阶段）期间，候选人将阐明 BMP 信号传导在神经嵴衍生间充质祖细胞和人 ES 衍生间充质干细胞 (MSC) 中调节软骨细胞分化的作用。 R00 期间拟议的研究之一将重点关注颅面发育过程中神经嵴衍生间充质祖细胞中 BMP 信号通过 ACVR1 对软骨细胞分化的调节。我们期望发现通过 ACVR1 过量 BMP 信号传导如何导致颅面骨骼畸形的新机制。 R00 期间的另一个项目将重点研究 BMP 信号如何通过 ACVR1 控制人 ES 衍生的 MSC 中软骨细胞分化的分子机制。我们期望发现有关 BMP 信号传导及其在从人类 ES 细胞有效生成软骨细胞中的实际作用的新信息。 这项研究具有重大的健康意义，因为颅面骨骼畸形是人类最常见的疾病之一。此外，这项研究还直接将紧急医疗保健联系起来，因为每年有超过一百万患者接受面部软骨重建相关手术，这是一种昂贵的治疗方法，因此需要建立利用人类 ES 细胞生成软骨细胞的策略。 公共健康相关性：该项目旨在阐明 BMP 信号传导在神经嵴细胞中软骨形成细胞命运决定中的功能。我们的研究将对人类颅面骨骼异常的分子发病机制产生新颖且重要的见解，并且还将为组织工程应用中从人类 ES 细胞中控制功能性软骨细胞的分化提供新技术。

项目成果

In situ hybridization methods for mouse whole mounts and tissue sections with and without additional β-galactosidase staining.

• DOI: 10.1007/978-1-60327-292-6_1
• 发表时间: 2014
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Komatsu, Yoshihiro;Kishigami, Satoshi;Mishina, Yuji
• 通讯作者: Mishina, Yuji

Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.

• DOI: 10.1002/jbmr.1857
• 发表时间: 2013-06
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Komatsu, Yoshihiro;Yu, Paul B.;Kamiya, Nobuhiro;Pan, Haichun;Fukuda, Tomokazu;Scott, Gregory J.;Ray, Manas K.;Yamamura, Ken-ichi;Mishina, Yuji
• 通讯作者: Mishina, Yuji

Establishment of left-right asymmetry in vertebrate development: the node in mouse embryos.

• DOI: 10.1007/s00018-013-1399-9
• 发表时间: 2013-12
• 期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
• 影响因子: 8
• 作者: Komatsu, Yoshihiro;Mishina, Yuji
• 通讯作者: Mishina, Yuji