The Role of Wnt Signaling in Normal and Abnormal Hematopoiesis

Wnt 信号转导在正常和异常造血中的作用

• 批准号: 10161560
• 负责人: Stephanie Laura Grainger
• 金额: $ 4.83万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-13 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161560
• 关键词: Adult; Affect; Area; Blood Cells; Bone Marrow; Book Chapters; California; Cancer Model; Cells; Collaborations; Communities; Complement; Complex; Core Facility; Cues; Development; Disease; Dysmyelopoietic Syndromes; Embryonic Development; Environment; Faculty; Genetic; Goals; Health care facility; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; In Vitro; Institutes; Institution; Investigation; Mesoderm; Paper; Pathway interactions; Production; Proteins; Publications; Research; Research Institute; Resources; Role; Running; Science; Scientist; System; Testing; Time; Training; Universities; Validation; Vascular blood supply; Visualization; WNT Signaling Pathway; Work; Zebrafish; cancer therapy; congenital blood disorder; hematopoietic stem cell fate; induced pluripotent stem cell; leukemia/lymphoma; novel; post-doctoral training; receptor; stem cell homeostasis; tool

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.

项目摘要 环境：大圣地亚哥地区的科学环境，圣地亚哥州立大学是 位置很好，很出色。除了圣地亚哥州立大学本身的资源和同事外， 几个世界级的研究机构在20分钟的车程内，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师经常与科学家合作，并利用护理设施，从 遍布圣地亚哥地区研究工作能够顺利进行，由于丰富的核心 任何科学领域的设施和专业知识。 候选人：格兰杰博士在加州大学的大卫特拉弗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。这种合作导致了 出版了三篇第一作者论文、一本书的章节、一篇评论论文和几篇合著论文。以下 这次培训，她准备好执行拟议的工作，并为高影响力的研究作出贡献， 科学界。 研究：所有成熟的血细胞都来源于造血干细胞（HSC）。体外产生HSC 从多能性前体中，这种诱导多能性干细胞将使我们能够治疗疾病， 白血病和淋巴瘤与体外衍生的造血干细胞，规避骨髓捐赠的需要。这 也将建立一个重要的细胞工具，了解造血的潜在机制， 疾病本提案的总体目标是更好地了解发展中国家的一个 从中胚层指示HSC命运的线索，Wnt信号级联。这项研究将在斑马鱼中进行， 其是用于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，并且 补充使用人类细胞进行机械验证。我假设早期Wnt/Fzd信号调节了 随后HSC扩增，这对成体HSC稳态有影响。特别是，我相信这个线索是 由一种新的受体复合物驱动我建议用1来检验这个假设。描述了这种受体 使用这些蛋白质的实时可视化，复合物导致Wnt信号。2.发现这如何影响 通过消除这种早期线索，在成年人中HSC内稳态。