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，为我们理解骨骼发育做出了贡献，以改善人类的颅面健康。本应用程序中描述了一个两倍的职业发展计划，包括（1）实质性的职业指导组成部分以及（2）将我的研究扩展到新的科学方向。提出的研究测试假设解决了有关骨骼细胞的两个令人兴奋的新概念，从而扩展了我已经在查尔斯·金梅尔（Charles Kimmel）博士实验室中已经大量的博士后工作。我的指导计划的第一个方面是增加了另一位高级科学家作为同事约翰·邮递员（John Postlethwait）博士，在我为独立准备时提供了新的见解。作为补充指导计划的一部分，金梅尔博士，Postlethwait博士和我本人还将每月开会，除了我与Kimmel博士的每周会议外。还将以一个咨询委员会的形式进行进一步的指导，该咨询委员会由俄勒冈大学教师朱迪思·艾森（Judith Eisen）博士（神经科学），Raghu Parthasarathy博士（物理）和Kryn Stankunas（Molecular Biology）博士组成。金梅尔和邮政局。在向更广泛的俄勒冈大学研究界的工作介绍后，我将在我的咨询委员会中与多样化的科学家小组见面。这些会议将有以下正式议程：早期奖励战略规划，中途校正，工作申请计划以及向独立过渡。我的指导的第三部分将是我参加神经科学助理教授指导计划。该计划通过科学写作和实验室管理技能为受训者提供指导。该计划通常保留给研究所的助理教授，学院主任肖恩·洛克里（Shawn Lockery）博士邀请我参加，这是一种荣幸。我职业发展计划的第二层涉及过渡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老鼠发育生物学。这些新的方向将补充我从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将需要出色的培训，我制定了一个系统的计划来促进这两种过渡。要学习基因组学和生物信息学，我将与我的同事紧密合作，该公司是该领域的创新者，并参加 俄勒冈大学生物信息学应用硕士课程的课程。这样我就可以将斑马鱼研究转化为小鼠系统，我将在两种不同的小鼠发育生物学家的实验室中结合一个正式的小鼠发育实验室课程。学习小鼠系统是我计划弥合斑马鱼工作和人类疾病之间差距的不可或缺的一部分。当我将所有这些方法结合在自己的实验室中时，这种协同方法的长期结局将更具影响力的科学。在本提案的研究部分中检验的假设涉及有关骨骼中细胞的两个新想法。首先，我建议祖细胞会做出一系列二元细胞命运的选择，从而导致骨骼细胞类型的多样性。其次，我提出了OE基因假设，以了解相关骨骼细胞彼此之间如何紧密相关的手段。在此提案中，我专注于假设的二元细胞自主选择，以成为韧带或骨细胞（AIM 1）。我解决了这种细胞命运的选择如何受遗传学和表观遗传学的影响（AIM 2）。我将斑马鱼的发现转化为鼠标模型，将斑马鱼中的发现与哺乳动物联系起来（AIM 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，例如鹰综合症。在本k99/R00中提出的仔细计划，彻底的指导和创新科学的结合肯定会为我提供独立途径。