Cell Fate Choices in the Skeleton

骨骼中细胞命运的选择

• 批准号: 9411214
• 负责人: James Tucker Nichols
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411214
• 关键词: Accounting; Address; Advisory Committees; Alpha Cell; Anatomy; Animals; Area; Award; Biochemistry; Bioinformatics; Bone Diseases; Cartilage; Cell Proliferation; Cells; Cellular biology; Color; Communities; Complement; DNA Modification Methylases; Development; Development Plans; Developmental Biology; Differentiated Gene; Disease; Eagles; Elements; Embryo; Enhancers; Epigenetic Process; Faculty; Fostering; Gene-Modified; Genes; Genetic; Genomics; Goals; Health; Human; Individual; Institutes; Job Application; Joints; Label; Laboratories; Learning; Life; Ligaments; Link; Location; Mammals; Mediating; Mentors; Mentorship; Modification; Molecular; Molecular Biology; Mus; Mutate; Mutation Analysis; Neural Crest Cell; Neurosciences; Oregon; Osteogenesis; Outcome; Pathway interactions; Penetrance; Phenotype; Physics; Population; Positioning Attribute; Primordium; Reporting; Research; Schools; Science; Scientist; Senior Scientist; Series; Signal Transduction; Site; Skeletal Development; Skeleton; Stem cells; Strategic Planning; Syndrome; System; Testing; Time; Tissues; Training; Transgenic Organisms; Translating; Transplantation; Universities; Vertebrates; Work; Writing; Zebrafish; bone; bone cell; career; career development; cell motility; cell type; chromatin remodeling; craniofacial; developmental genetics; experimental study; field study; gene discovery; gene function; human disease; improved; innovation; insight; laboratory curriculum; meetings; molecular marker; mouse development; mouse model; mutant; professor; progenitor; programs; public health relevance; reverse genetics; skeletal; skills; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): My long-term career goal is to become a successful independent scientist contributing to our understanding of skeletal development in order to improve human craniofacial health. A two-fold career development plan is described in this application including (1) a substantial career mentorship component and (2) expanding my research in new scientific directions. The proposed research tests hypotheses addressing two exciting new concepts regarding skeletal cells, extending my already substantial body of postdoctoral work in the laboratory of Dr. Charles Kimmel. The first aspect of my mentorship plan is the addition of another senior scientist as a co-mentor, Dr. John Postlethwait, providing fresh insight as I prepare for independence. As part of a complementary mentorship plan, Dr. Kimmel, Dr. Postlethwait and myself will meet monthly, in addition to my weekly meetings with Dr. Kimmel. Further mentorship will occur in the form of an Advisory Committee consisting of the University of Oregon faculty Dr. Judith Eisen (Neuroscience), Dr. Raghu Parthasarathy (Physics), and Dr. Kryn Stankunas (Molecular Biology), in addition to Drs. Kimmel and Postlethwait. I will meet biannually with the diverse group of scientists in my Advisory Committee following a presentation of my work to the broader University of Oregon research community. These meetings will have the following formal agendas: early award strategic planning, mid-course correction, job application planning, and transition to independence. The third portion of my mentorship will be my participation in the Institute of Neuroscience Assistant Professor Mentorship Program. This program provides mentees guidance with scientific writing, and lab management skills. The program is normally reserved for assistant professors in the institute and it is an honor that Dr. Shawn Lockery, the institute director, invited me to participate. The second tier of my career development plan involves a transition into several new areas of research including the fields of genomics & bioinformatics, as well as mouse developmental biology. These new directions will complement my existing expertise in cell biology and biochemistry from graduate school, and zebrafish developmental genetics from my postdoctoral studies. A segue into two new fields of study will require excellent training and I have a systematic plan in place to foster both of these transitions. To learn genomics & bioinformatics, I will work closely with my co-mentor that is an innovator in the field, and attend courses in the Bioinformatics Applied Masters program at the University of Oregon. So that I may translate my zebrafish studies into the mouse system, I will combine a formal intensive laboratory course in mouse development with training in the labs of two different mouse developmental biologists. Learning the mouse system is an integral part of my plan to bridge the gap between my zebrafish work, and human disease. The long-term outcome of this synergistic approach will be profoundly more impactful science when I combine all of these approaches in my own laboratory. The hypotheses tested in the research portion of this proposal address two new ideas about cells in the skeleton. First, I propose that a progenitor cell makes a series of binary cell fate choices resulting in the diversity of skeletal cell types. Second, I propose the oe gene away hypothesis as a means to understand how closely related skeletal cells are to each other. In this proposal, I focus on a hypothetical binary, cell autonomous choice to become either a ligament or a bone cell (Aim 1). I address how this cell fate choice is influenced by genetics and epigenetics (Aim 2). I will translate my zebrafish findings into the mouse model, linking my discoveries in the zebrafish to mammals (Aim 3). This work will impact our understanding of human craniofacial diseases involving ligaments and bones, such as Eagle's syndrome. The combination of careful planning, thorough mentorship, and innovative science proposed in this K99/R00 are certain to provide me with a pathway to independence.

描述（由申请人提供）：我的长期职业目标是成为一名成功的独立科学家，为我们对骨骼发育的理解做出贡献，以改善人类颅面健康。在本申请中描述了一个双重职业发展计划，包括（1）大量的职业导师组成部分和（2）在新的科学方向扩展我的研究。拟议的研究测试假设解决两个令人兴奋的新概念，关于骨骼细胞，扩展我已经大量的博士后工作在博士的实验室。我的导师计划的第一个方面是增加了另一位资深科学家作为共同导师，约翰·波斯尔思韦特博士，在我为独立做准备时提供新的见解。作为补充指导计划的一部分，Kimmel博士，Postlethwait博士和我本人除了每周与Kimmel博士会面外，还将每月会面。进一步的指导将以咨询委员会的形式进行，该委员会由俄勒冈州大学的教师Judith Rathen博士（神经科学）、Raghu Parthasarathy博士（物理学）和Kryn Stankunas博士（分子生物学）以及Kimmel和Postlethwait博士组成。在向更广泛的俄勒冈州大学研究界介绍我的工作之后，我将每两年与咨询委员会中的不同科学家小组会面。这些会议将有以下正式议程：早期奖励战略规划，中期纠正，工作申请规划和向独立过渡。我的导师的第三部分将是我在神经科学助理教授导师计划研究所的参与。该计划为学员提供科学写作和实验室管理技能的指导。这个项目通常是为研究所的助理教授保留的，研究所所长肖恩·洛克里博士邀请我参加是一种荣誉。我的职业发展计划的第二层涉及到几个新的研究领域，包括基因组学和生物信息学领域，以及小鼠发育生物学。这些新的方向将补充我在研究生院的细胞生物学和生物化学方面的现有专业知识，以及我博士后研究的斑马鱼发育遗传学。进入两个新的研究领域需要出色的培训，我有一个系统的计划来促进这两个过渡。为了学习基因组学和生物信息学，我将与我的共同导师密切合作，他是该领域的创新者，并参加 在俄勒冈州大学的生物信息学应用硕士课程。为了将我对斑马鱼的研究转化到小鼠系统中，我将联合收割机结合小鼠发育的正式强化实验室课程和两个不同小鼠发育生物学家的实验室培训。学习老鼠系统是我计划的一个组成部分，我的计划是弥合我的斑马鱼研究和人类疾病之间的差距。当我在自己的实验室里将所有这些方法联合收割机结合起来时，这种协同方法的长期结果将是更有影响力的科学。在本提案的研究部分测试的假设解决了两个关于骨骼细胞的新想法。首先，我认为祖细胞做出一系列二元细胞命运选择，导致骨骼细胞类型的多样性。第二，我提出oe基因消失假说作为一种手段来了解骨骼细胞之间的关系有多密切。在这个建议中，我专注于一个假设的二元，细胞自主选择成为韧带或骨细胞（目标1）。我解决了这种细胞命运的选择是如何影响遗传学和表观遗传学（目的2）。我将把我在斑马鱼身上的发现转化为小鼠模型，将我在斑马鱼身上的发现与哺乳动物联系起来（目标3）。这项工作将影响我们对涉及韧带和骨骼的人类颅面疾病的理解，如鹰氏综合征。K99/R 00中提出的精心计划，彻底的指导和创新科学的结合肯定会为我提供一条独立的道路。