Cell Fate Choices in the Skeleton

描述(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，为我们了解骨骼发育做出贡献，以改善人类颅面健康。在这份申请中描述了一个双重的职业发展计划，包括(1)实质性的职业指导部分和(2)在新的科学方向上扩展我的研究。这项拟议的研究测试了两个关于骨骼细胞的令人兴奋的新概念的假设，扩展了我在Charles Kimmel博士实验室的大量博士后工作。我的导师计划的第一个方面是增加了另一位资深科学家约翰·波斯尔斯韦特博士作为共同导师，在我准备独立的时候提供了新的见解。作为互补性指导计划的一部分，除了每周与基梅尔博士会面外，基梅尔博士、波斯尔斯韦特博士和我自己还将每月见面。进一步的指导将以咨询委员会的形式进行，咨询委员会由俄勒冈大学教员朱迪思·艾森博士(神经科学)、拉古·帕塔萨拉西博士(物理学)和克里恩·斯坦库纳斯博士(分子生物学)组成，此外还有基梅尔博士和波斯尔斯韦特博士。在向更广泛的俄勒冈大学研究界介绍我的工作后，我将每两年与我的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、中期更正、工作申请规划和向独立的过渡。我的导师生涯的第三部分将是我参加神经科学研究所助理教授导师计划。该项目为学员提供科学写作指导和实验室管理技能。该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，以及小鼠发育生物学。这些新方向将补充我研究生院在细胞生物学和生物化学方面的现有专业知识，以及我博士后研究中斑马鱼发育遗传学的现有专业知识。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，我将与我的合作导师密切合作，他是该领域的创新者，并参加 俄勒冈大学生物信息学应用硕士课程。为了将我的斑马鱼研究转化为老鼠系统，我将把关于老鼠发育的正式强化实验室课程与两个不同的老鼠发育生物学家的实验室培训结合起来。学习鼠标系统是我弥合斑马鱼工作和人类疾病之间差距的计划的组成部分。当我在自己的实验室中将所有这些方法结合在一起时，这种协同方法的长期结果将是更有影响力的科学。在这项提案的研究部分测试的假设解决了关于骨骼中细胞的两个新想法。首先，我认为祖细胞做出了一系列的二元细胞命运选择，导致了骨骼细胞类型的多样性。其次，我提出了OE基因离开假说，以此作为了解骨骼细胞彼此之间关系有多密切的一种手段。在这项提议中，我的重点是一个假设的二元细胞自主选择成为韧带或骨细胞(目标1)。我将阐述遗传学和表观遗传学如何影响这种细胞命运选择(目标2)。我将把我在斑马鱼上的发现转化为老鼠模型，将我在斑马鱼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头面部疾病的理解，例如鹰综合征。在K99/R00中提出的周密的计划、彻底的指导和创新的科学相结合，肯定会为我提供一条独立的道路。

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.