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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

基本信息

批准号：
10441685
负责人：
Stephanie Laura Grainger
金额：
$ 39.7万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441685
关键词：
Acute Myelocytic Leukemia Adult Affect Animal Model Animals Antibodies Aorta Area Award Biochemical Biological Assay Biological Sciences Blood Blood Cells Bone Marrow CRISPR/Cas technology California Cancer Model Cell Cycle Cell Separation Cell Therapy Cells Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communities Conflict (Psychology)Core Facility Cues Data Defect Development Developmental Biology Disease Doctor of Philosophy Dysmyelopoietic Syndromes Embryonic Development Environment Fishes Gene Expression Gene Expression Profiling Genetic Genetic Transcription Goals Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Histology Human In Vitro Institutes Institution Investigation Knock-out Lead Leadership Ligands MLL-AF9 Malignant - descriptor Malignant Neoplasms Mediating Mesoderm Modeling Motivation Pathway interactions Patients Phase Phenotype Postdoctoral Fellow Process Production Protocols documentation Publications Publishing Reporting Research Role Running Science Scientist Senior Scientist Series Signal Transduction Specificity Stem Cell Development System Testing Time Tissues Training Universities Vascular blood supply Vertebrates Visualization WNT Signaling Pathway WNT9A gene Walking Work Zebrafish base cancer therapy career career development cell type congenital blood disorder driving force gain of function genetic manipulation hematopoietic stem cell expansion hematopoietic stem cell fate hematopoietic stem cell niche induced pluripotent stem cell innovation knock-down leukemia leukemia/lymphoma leukemic stem cell mouse model mutant neoplastic new therapeutic target next generation novel receptor recruit self renewing cell skills stem cell function stem cell homeostasis stem cell proliferation stem cells therapeutic development tissue stem cells tool transcriptome transcriptome sequencing

项目摘要

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.

项目概要环境：加州大学（UC）是一所领先的学术研究机构，高级科学家们在加州大学有着培养下一代科学家的悠久传统，其中百分之七的科学家每年授予全国博士学位，有超过 6000 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讨论、培训和阐述，索尔克学院和桑福德伯纳姆学院均在步行范围内。 Grainger 博士可以接触到多种培训课程、课程和研讨会，以促进个人发展并扩展她的科学和领导力技能。此外，每周还有大量的职业发展研讨会可供参加无数的科学研讨会。由于资源丰富，研究工作能够在这里顺利进行任何科学领域都可以获得核心设施和专业知识。候选人：Grainger 博士是加州大学圣地亚哥分校 David Traver 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 信号传导和动物模型方面拥有深厚的背景。过去3.5年里，她一直与加州大学圣地亚哥分校 Karl Willert 博士的实验室合作，出版了两本出版物：一本现已发表在 Cell Reports 上；第二个目前正在 Zebrafish 上印刷。 Grainger 博士是该领域的领导者实验室，建立了这个项目，并成为 Traver-Willert 合作努力的驱动力团体。她也是实验室外的领导者，在那里她组织了一个专注于干细胞的博士后研讨会系列细胞，丰富了她周围的社区。她已做好准备执行拟议的工作，实现她的职业生涯发展和培训目标，并为科学界贡献高影响力的研究。研究：所有成熟的血细胞均源自造血干细胞（HSC）。体外生成 HSC 来自多能前体的诱导多能干细胞将使我们能够治疗诸如利用体外衍生的 HSC 来治疗白血病和淋巴瘤，从而避免了骨髓捐赠的需要。这还将建立一个重要的细胞工具来理解造血的潜在机制疾病。该提案的总体目标是更好地了解其中一项发展指示中胚层 HSC 命运的线索，即 Wnt 信号级联。这项研究将在斑马鱼中进行，这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，这对成年 HSC 稳态有影响。我建议通过 1. 表征所需的 Wnt/Fzds，2. 确定会发生什么来检验该假设 3. 发现该信号在转录组水平的下游如何影响 HSC 稳态。