The Role of Wnt Signaling in Normal and Abnormal Hematopoiesis

项目摘要 环境：圣地亚哥州立大学所在的大圣地亚哥地区的科学环境 所在的位置，是杰出的。除了圣地亚哥州立大学本身的资源和同事之外，还有 在20分钟的车程内有几个世界级的研究机构，包括加州大学旧金山分校 迭戈、斯克里普斯研究所、索尔克研究所和桑福德-伯纳姆-普雷比研究所。 圣地亚哥州立大学的教职员工经常与科学家合作，并利用来自 遍布圣地亚哥地区。由于这里有丰富的岩心，研究工作得以顺利进行。 任何科学领域都有可用的设施和专业知识。 候选人：格兰杰博士在加州大学大卫·特拉弗的实验室完成了博士后培训， 在圣地亚哥，她与卡尔·威勒特博士的实验室密切合作。这一合作导致了 发表了三篇第一作者论文、一本书章节、一篇评论论文和几篇合著者论文。跟随 在这次培训中，她做好了执行拟议工作的准备，并为 科学界。 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，并具有保守的遗传学，以及 辅以使用人体细胞进行机械验证。我推测，早期的WNT/FZD信号调节 后来HSC扩增，这对成年HSC的动态平衡有影响。特别是，我认为这条线索是 由一种新的受体复合体驱动。我建议通过1来检验这一假设。描述这种受体是如何 复杂的导致Wnt信号使用这些蛋白质的实时可视化。2.发现这一点如何影响 通过去除这一早期线索，成年体内的HSC动态平衡。

Project Summary Environment: The scientific environment in the Greater San Diego area, where San Diego State University is located, is outstanding. In addition to the resources and colleagues at San Diego State University itself, there are several world-class research institutions within a 20-minute drive, including the University of California San Diego, The Scripps Research Institute, The Salk Institute, and the Sanford-Burnham-Prebys Research Institutes. Faculty at San Diego State University routinely collaborate with scientists, and make use of care facilities, from all over the San Diego area. 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 completed her postdoctoral training in David Traver’s lab at the University of California, San Diego, where she worked in close collaboration with Dr. Karl Willert’s lab. This collaboration led to the publication of three first author papers, a book chapter, a review paper and several co-author papers. Following this training, she is well poised to execute the proposed work 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, and complemented using human cells for mechanistic validation. I hypothesize that an early Wnt/Fzd cue regulates later HSC amplification, which has an impact on adult HSC homeostasis. In particular, I believe that this cue is driven by a novel receptor complex. I propose to test this hypothesis by 1. Characterizing how this receptor complex leads to a Wnt signal using real-time visualization of these proteins. 2. Discovering how this affects HSC homeostasis in the adult by removing this early cue.