Pro-inflammatory cytokines in hematopoietic stem cell function

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DESCRIPTION (provided by applicant): Candidate: Eric M. Pietras is a postdoctoral scholar who received his Ph.D. at the University of California, Los Angeles (UCLA) for work characterizing intracellular pathogen detection mechanisms and the role of pro- inflammatory cytokines in orchestrating the mobilization of immune cells in response to bacterial infection. His research in the laboratory of Dr. Genhong Cheng identified the pro-inflammatory cytokines interleukin (IL)-1 and interferon (IFN)-gamma as key inducers of myeloid cell recruitment following in vivo bacterial challenge in mice. As a postdoctoral scholar in the laboratory of Dr. Emmanuelle Passegue at the University of California, San Francisco (UCSF), he has continued to investigate the function of these pro-inflammatory cytokines but in the context of normal and leukemic hematopoiesis. Using mouse models of human myeloproliferative neoplasms (MPNs), he showed that MPNs are associated with increased systemic levels of many pro- inflammatory cytokines, and helped demonstrate their key roles in promoting disease pathogenesis by altering the biology of hematopoietic progenitors and cells in the BM niche. He is now focused on understanding the role of type I interferons (IFN-1s) and IL-1 in regulating hematopoietic stem cell (HSC) function and fate choice. The candidate's short-term goal is to continue his mentored studies to develop his independent line of research and obtain further training in bioinformatics, single-cell expression analysis, and single-cell time lapse microscopy, with a long-term goal of understanding how the systemic cytokine milieu affects HSC biology at steady state and during chronic inflammation, as an independent faculty researcher. Environment: The proposed work will take place in the laboratory of Dr. Emmanuelle Passegue, in the Department of Medicine, Division of Hematology/Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, a world-class biomedical research university. The mentor's laboratory is highly respected in the field of HSC biology and has been very productive in using mouse models of human hematological malignancies to study the biology of normal and transformed HSCs. The candidate has access to significant resources at UCSF, including dedicated cell sorting facility and an array of cores for mouse work, microscopy, and cell culture. The candidate will receive guidance and scientific training from Dr. Passegue, and has designated a co-mentor, Dr. Jason Cyster, a highly accomplished immunologist who specializes in the study of systemic immune cell trafficking. He has also established a strong collaboration with Dr. Timm Schroeder at the Swiss Institute of Technology, who developed pioneering single-cell tracking techniques that will be used in the proposed work. He has also assembled a mentorship committee composed of established leaders from UCSF to oversee and enhance his mentored training experience. Research: Hematopoietic stem cells (HSCs) are a rare population of self-renewing bone marrow (BM) cells that generate all mature lineages of blood cell for the lifetime of an organism. HSCs are typically kept in a dormant state, they are capable of rapidly entering the cell cycle and differentiating to produce needed mature progeny in response to infection or injury. While such stresses are associated with the production of a complex array of inflammatory cytokines by mature immune cells and other tissues, the direct effects of these pro- and anti-inflammatory cytokines on the biology of HSCs remain largely unknown. Moreover, the extent to which systemic levels of inflammatory cytokines regulate HSC homeostasis has not been extensively explored. This is particularly true in the context of chronic inflammatory diseases, a range of conditions where elevated levels of pro-inflammatory cytokines may alter HSC self-renewal and differentiation activities, hence leading to the degraded HSC function observed in human patients. Our preliminary data suggest that pro-inflammatory cytokines such as IL-1 and IFN-1s have profound effects on HSC fate choices and alter survival, differentiation and self-renewal activities. Here, we propose to comprehensively investigate the effects of IL-1 and IFN-1s, as well as the anti-inflammatory cytokine IL-10, on HSC function and homeostasis using the mouse as a highly conserved model of hematopoiesis. In Aim 1, we will assess how IL-1, IFN-1s, and IL-10 direct HSC fate choices and affect the molecular networks governing HSC differentiation and self-renewal. In Aim 2, we will address the roles of IL-1, IFN-1s, and IL-10 in regulating steady-state HSC homeostasis and their response to acute stress using Ifnar-/-, Il1r1-/-, and Il10-/- mice. We will also examine how these cytokines affect the interaction between HSCs and their BM niche and their role in governing HSC function. In Aim 3, we will explore how chronic IFN-1- and IL-1-driven inflammation degrades HSC function in vivo. We will assess how exposure to chronic inflammation alters the molecular networks regulating HSC function and whether blockade of pro-inflammatory IFN-1 and IL-1 signaling can revert these deleterious effects and restore HSC fitness and blood production. Taken together, these exciting studies will greatly enhance our understanding of the critical relationship between inflammation and hematopoiesis, and will provide a basis for therapies aimed at restoring normal HSC function in patients suffering from chronic inflammatory diseases.