2011 |
Pietras, Eric M |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Regulation of Normal and Leukemic Hematopoiesis by Type I Interferon @ University of California, San Francisco
DESCRIPTION (provided by applicant): The goals of this project are to define the mechanisms by which type I IFNs alter the fates of immature hematopoietic stem cells (HSCs) and progenitor cells, and to identify the effect and underlying mechanisms of type I IFNs on the health and potential of normal and leukemic HSCs. These studies will be carried out using HSCs and progenitor cells isolated from wild-type mice and from the SCLtTAxBCR/ABL double transgenic mouse model of human chronic myelogenous leukemia (CML), and a comprehensive array of in vivo and in vitro experimental approaches. In the first aim, we will investigate how short-term (days) and long-term (weeks) exposure to type I IFNs affects the biology of HSCs and progenitor cells with respect to their quiescence, proliferation, potential, and susceptibility to apoptosis. We will also examine whether chronic (months) exposure to type I IFNs damages HSC self-renewal. Lastly, we will define the molecular mechanisms underlying these changes. In the second aim, we will assess how type I IFNs affect the biology of leukemic HSCs and progenitor cells compared to wild type cells. We will investigate how the deregulated properties of BCR/ABL-expressing leukemic HSCs (i.e., increased proliferation, decreased quiescence, increase survival) change their response to type I IFNs exposure and may sensitize them to combinatorial treatments with type I IFNs and the BCR/ABL tyrosine kinase inhibitor, Imatinib. Taken together, these approaches should uncover how inflammatory signals such as type I IFNs impact on the regulatory networks that normally control HSC and progenitor cell homeostasis, and how the deregulated properties of leukemic HSCs may alter their sensitivity to the effects of inflammatory signals and therapeutic interventions. PUBLIC HEALTH RELEVANCE: This project seeks to understand how type I interferons (IFNs), a large family of inflammatory proteins, affects the biology of hematopoietic stem cells (HSCs), a small population of bone marrow cells that generate all blood cells. Improper regulation of HSC activity can lead to a number of severe blood diseases. These include chronic myelogenous leukemia (CML), which has long been treated with type I IFNs despite the lack of knowledge regarding their mechanism of action. Recent clinical work suggests that type I IFNs may enhance the curative effect of other CML treatments, such as the tyrosine kinase inhibitor Imatinib. By uncovering how type I IFNs affect the biology of normal and leukemic HSCs, and the molecular mechanisms underlying these effects, the proposed work could be of significant value to public health by providing the basis for the design of more effective co-treatments for CML and other blood diseases that will harness the beneficial effect of type I IFNs.
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0.972 |
2014 — 2018 |
Pietras, Eric M |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Pro-Inflammatory Cytokines in Hematopoietic Stem Cell Function @ University of California, San Francisco
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.
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0.972 |
2019 — 2021 |
Pietras, Eric M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Impact of Il-1 Signaling On Hematopoietic Stem Cell Function and Emergence of Clonal Hematopoiesis. @ University of Colorado Denver
PROJECT SUMMARY The long-term objective of this proposal is to identify mechanism(s) that promote clonal hematopoiesis of indeterminate potential (CHIP). CHIP is a risk factor for cardiovascular disease, myeloid hematological malignancy, and all-cause mortality. CHIP is thought to arise from mutant hematopoietic stem cells (HSC) carrying oncogenic mutations that endow the cells with increased fitness, leading to expansion of the mutant clone. Rare hematopoietic clones carrying CHIP-associated mutations are near-ubiquitous in healthy individuals. However, CHIP is largely confined in older individuals or patients with a history of smoking, chemo- or radiotherapy exposure. This suggests that physiological perturbation(s) unique to aging and genotoxin exposure, such as chronic inflammation, are required to drive CHIP. To better understand the mechanism underlying CHIP, we have conducted mouse studies that indicate chronic IL-1 production in the BM is a common consequence of aging and exposure to radiation or chemotherapy. Our preliminary data show that chronic IL-1 activates a cell growth arrest program associated with PU.1 induction in long-term HSC (HSCLT). Strikingly, Tet2-deficient HSCLT fail to fully activate this growth arrest program during IL-1 exposure. Along these lines, our data show that increased Tet2-deficient clonal expansion requires chronic IL-1. These preliminary data suggest that clonal expansion of mutant HSC is an emergent feature dependent on chronic inflammation. The studies proposed here will identify and characterize the molecular and cellular mechanisms by which chronic IL-1 promotes mutant HSC clonal expansion, using Tet2-deficiency as a model. Lines of investigation will include molecular and cellular analyses of normal and Tet2-deficient HSC exposed to IL-1, and competitive transplant assays to assess the functional impact of chronic IL-1 on normal and Tet2-deficient HSC fitness side-by-side. Lastly, experiments will assess whether IL-1 blockade can restore normal HSC fitness and reverse or limit clonal expansion. Altogether, our investigations could provide a basis for redefining CHIP as a potentially reversible process of somatic evolution in which an inflammatory BM environment selects for mutant HSC clones.
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0.943 |