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

描述（由申请人提供）：这是一份美国国立卫生研究院独立之路奖（K99/R00）资助提案，旨在促进密歇根大学牙科学院研究员小松义宏博士进入独立研究岗位。候选人是一名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有着重要的研究记录，用于解决人类出生缺陷和先天性疾病的病因。他的目标是获得终身教职，并在颅面骨骼畸形和人类胚胎干细胞软骨/骨组织再生领域建立自己的研究项目。在指导期内（本奖项的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而协作的环境中工作，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期，候选人将研究BMP信号通过BMP I型受体ACVR1的作用，以阐明颅面发育过程中神经嵴细胞中软骨细胞命运的决定。同时，候选人将接受人类胚胎干细胞实验技术的培训，并制定其合理的研究策略。此外，候选人将增加他对颅面发育研究的补充分析方法的库存。这些成就将是通往独立（R00）阶段的基础桥梁。在独立（R00期），候选人将阐明BMP信号在神经嵴源性间充质祖细胞和人es源性间充质干细胞（MSC）中调节软骨细胞分化的作用。R00期间提出的一项研究将重点关注颅面发育过程中神经嵴源间充质祖细胞中BMP信号通过ACVR1调控软骨细胞分化。我们期望发现通过ACVR1过量BMP信号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关注BMP信号如何通过ACVR1调控人类es来源的MSC中软骨细胞分化的分子机制。我们期待发现关于BMP信号及其在人类胚胎干细胞有效生成软骨细胞中的实际作用的新信息。颅面骨骼畸形是人类最常见的疾病之一，因此本研究具有重要的健康相关性。此外，每年有超过100万名患者接受与面部软骨重建相关的手术，这是一项昂贵的治疗，因此，该研究直接连接了建立利用人类胚胎干细胞生成软骨细胞策略所需的紧急医疗保健。

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.