The Role of Wnt Signaling in Normal and Abnormal Hematopoiesis

项目摘要 环境：加州大学(UC)是一所领先的学术研究机构， 科学家在加州大学培养下一代科学家的传统由来已久，那里有7%的人 S博士每年获奖，6000多名博士后选择 进行他们的研究。加州大学圣地亚哥分校(UCSD)是关键组成部分，擅长协作和 创新的生物科学。这里的环境充满了科学的讨论、培训和展示， 索尔克学院和桑福德-伯纳姆学院步行即可到达。格兰杰博士有权接触到各种各样的 培训课程、课程和研讨会，用于个人发展和扩大她的科学和领导能力 技能。此外，每周都有大量的职业发展研讨会可供参加。 去参加无数的科学研讨会。研究工作之所以能够在这里顺利进行，是因为有丰富的 任何科学领域都有的核心设施和专业知识。 候选人：格兰杰博士是加州大学圣地亚哥分校大卫·特拉弗实验室的博士后研究员，他的最终职业目标是 在R1大学领导一个专注于干细胞的研究实验室。她被招募加入特拉弗博士的实验室是因为 她在发育生物学、WNT信号和动物模型方面有很强的背景。在过去的3.5年里， 她一直在与加州大学圣地亚哥分校卡尔·威勒特博士的实验室合作，这导致了两本书的出版：一本 现已在《细胞报告》上发表；第二本目前正在斑马鱼出版。格兰杰博士是这一领域的领导者 实验室，建立了这个项目，并成为Traver-Willert合作努力的推动力 一群人。她也是实验室之外的领导者，在那里她组织了一系列专注于STEM的博士后研讨会 细胞，丰富了她周围的社区。她已经准备好执行拟议的工作，实现她的职业生涯 发展和培训目标，并向科学界贡献具有重大影响的研究成果。 研究：所有成熟血细胞均来源于造血干细胞(HSCs)。肝星状细胞的体外生成 从多能前体细胞中诱导的多能干细胞将使我们能够治疗以下疾病 白血病和淋巴瘤与体外来源的造血干细胞，绕过了骨髓捐赠的需要。这 也将建立一个重要的细胞工具来理解造血的潜在机制 疾病。这项建议的首要目标是更好地了解发展中的 指示中胚层HSC命运的信号，Wnt信号级联。这项研究将在斑马鱼身上进行， 它们是直接可视化血液干细胞的理想系统，并且具有保守的遗传学。我假设 早期的Wnt/Fzd信号调节后来的HSC扩增，这对成人HSC的动态平衡有影响。我 建议通过1.描述所需的WNT/FZD，2.确定发生的情况来检验这一假设 该信号下游的转录组水平和3。发现如何影响HSC的动态平衡。

Project Summary Environment: The University of California (UC) is a leading academic research institution where senior scientists have a long-standing tradition of training the next generation of scientists at UC, where seven percent of the nation’s Ph.D.’s are awarded each year and more than six thousand post-doctoral fellows choose to conduct their research. The UC campus in San Diego (UCSD) is key component, excelling at collaborative and innovative biological science. The environment here is rich in scientific discussion, training and exposition, with the Salk and Sanford-Burnham institutes within walking distance. Dr. Grainger has access to a wide variety of training sessions, classes and seminars for personal development and expansion of her scientific and leadership skills. There are a wealth of career development seminars available to be attended on a weekly basis, in addition to the innumerable scientific seminars. Research efforts are able to run smoothly here, due to the abundance of core facilities and expertise available in any area of science. Candidate: Dr. Grainger is a postdoctoral fellow in David Traver’s lab at UCSD whose ultimate career goal is to lead a research lab focused on stem cells at an R1 University. She was recruited to join Dr. Traver’s lab because of her strong background in developmental biology, Wnt signaling and animal models. Over the past 3.5 years, she has been working in collaboration with Dr. Karl Willert’s lab at UCSD, which has led to two publications: One is now published at Cell Reports; the second is currently in press at Zebrafish. Dr. Grainger is a leader in the lab, having established this project and being the driving force of the collaborative efforts of the Traver-Willert group. She is also a leader outside of the lab, where she organizes a postdoc seminar series focused on stem cells, enriching the community around her. She is well poised to execute the proposed work, achieve her career development and training goals and to contribute high impact research to the scientific community. Research: All mature blood cells are derived from hematopoietic stem cells (HSCs). Generating HSCs in vitro from pluripotent precursors such induced pluripotent stem cells would allow us to treat diseases such as leukemias and lymphomas with in vitro derived HSCs, circumventing the need for bone marrow donation. This would also establish an important cellular tool for understanding the underlying mechanisms of hematopoietic diseases. The overarching goal of this proposal is to gain a better understanding of one of the developmental cues that instruct HSC fate from mesoderm, the Wnt signaling cascade. This study will be conducted in zebrafish, which are an ideal system for direct visualization of blood stem cells and have conserved genetics. I hypothesize that an early Wnt/Fzd cue regulates later HSC amplification, which has an impact on adult HSC homeostasis. I propose to test this hypothesis by 1. Characterizing the Wnt/Fzds required, 2. Determining what happens downstream of this signal at the transcriptome level and 3. Discovering how this affects HSC homeostasis.