The Role of Wnt Signaling in Normal and Abnormal Hematopoiesis

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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.