The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
Principal Investigator: KATHERINE YUDEH KING
Abstract: DESCRIPTION (provided by applicant): The Candidate: I am highly motivated and exceptionally qualified to pursue a career in academic medicine in the field of Pediatric Infectious Diseases. A graduate of Harvard University, the Medical Scientist Training Program at Washington University in St. Louis, and the Pediatrics Residency Program at Baylor College of Medicine (BCM), I have pursued excellence throughout my academic training. I am motivated by a desire to improve the medical care of children with infectious diseases, both in the United States and throughout the world. I believe that advances in care will arise from studying the interactions between pathogens and the host immune response. Cells of the host immune response are ultimately derived from hematopoietic stem cells (HSCs) in bone marrow. I have capitalized on the institutional strength of BCM in the field of stem cell biology to pursue hematopoietic stem cell research during my fellowship. I intend to combine my prior experience in microbial pathogenesis with stem cell research to study the effect of infections on HSC function. This research will have immediate application for patients recovering from bone marrow transplantation. Furthermore, this work will lead to insight and potential interventions for myelosuppression as a result of chronic infections such as severe viral infections and tuberculosis. Research Career Development Plan: I will utilize an array of educational and research resources in Houston to strengthen my research career development. Within the BCM graduate programs in biomedical sciences, I will enroll in courses on new research in cancer biology and immunology. I will gain expertise in biostatistics, research conduct and ethics, and state-of-the-art technology in microscopy and flow cytometry. I will participate in local, national, and international meetings in the fields of infectious diseases, immunology, and stem cell biology. I have established a collaboration with hematologist-oncologists at Texas Children's Hospital and will work with them to study the effects of infection on human bone marrow samples. Beyond these training activities, I will continue my highly productive research fellowship with my mentor Dr. Margaret Goodell. Dr. Goodell is a nationally recognized stem cell biologist with expertise in regulation of hematopoietic stem cells. While she directs a very productive research group, Dr. Goodell is also recognized for her mentoring skills and is the PI on a recently renewed T32 grant. Dr. Goodell has provided me the full complement of research tools, space, and scientific guidance that will ensure my success as I transition into an independent research career. Furthermore, BCM and my department of Pediatric Infectious Diseases have invested in my research career development by assuring me 100% protected time in a tenure-track assistant professor position at the completion of my fellowship during the first two years of the grant period. Research Project: During an infection, peripheral immune cells are consumed and must be replenished by progenitor cells. Hematopoietic stem cells (HSCs) are the earliest of these progenitors, and they maintain pluripotency and self-renewal potential throughout the life of an organism. Surprisingly little is known about how HSCs sense and respond to systemic infection. In this proposal, I describe the use of a mouse model of chronic Mycobacterium avium infection to understand changes in HSC function triggered by the innate immune response. My preliminary data suggest that HSCs are activated to proliferate during M. avium infection, and that the process is dependent on interferon-3 (IFN3) and its downstream effector Irgm1 (Immunity-related GTPase M). I propose to delineate the role of IFN3 in the HSC response to infection by conducting M. avium infections in mice lacking components of the IFN3 signaling pathway, including IFN3, IFN3R1, and Stat1- deficient mice. Furthermore, I will determine whether HSC proliferation can be triggered by IFN3 stimulation alone. Since the interferon-inducible protein Irgm1 is known to participate in autophagy in murine macrophages, we suspected and confirmed that autophagy occurs in HSCs of infected mice. To further explore this finding, we propose to investigate whether autophagy is dependent on Irgm1 in murine HSCs, and whether this process participates in HSC regulation. Specifically, we will investigate whether autophagy occurs in HSCs of infected Irgm1-deficient mice, and we will determine if HSC proliferation and/or function change in the presence of inhibitors of autophagy. Finally, we will determine whether interferon signaling and autophagy have functional significance for human HSCs isolated from bone marrow transplant patients. The significance of these studies is that they will elucidate the mechanisms by which the immune system triggers replenishment of the pool of peripheral immune cells during infection. Understanding the immediate and long-term effects of infection on HSCs has direct implications for treatment of patients recovering from bone marrow transplantation. Furthermore, these studies will lead to critical information about use of interferons or inhibitors of autophagy as therapeutic agents for aplastic anemia and myelosuppression due to severe viral and mycobacterial infections. My work and future career will focus on how HSCs respond to infection, a basic physiologic response that can be aberrant in disease states, disrupted by infectious pathogens, or co-opted for therapeutic purposes.
Funding Period: 2010-05-01 - 2015-02-28
more information: NIH RePORT
- Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infectionMegan T Baldridge
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
Nature 465:793-7. 2010..Our studies contribute to a deeper understanding of haematological responses in patients with chronic infections such as HIV/AIDS or tuberculosis...
- Inflammatory signals regulate hematopoietic stem cellsMegan T Baldridge
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Trends Immunol 32:57-65. 2011..Observing the biology of HSCs through the lens of infection and inflammation has led to the discovery of an array of immune-mediators that serve crucial roles in HSC regulation and function...
- Irgm1 protects hematopoietic stem cells by negative regulation of IFN signalingKatherine Y King
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Blood 118:1525-33. 2011..The deleterious effects of excessive IFN signaling may explain how hematologic abnormalities arise in patients with inflammatory conditions...
- Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune responseKatherine Y King
Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Alkek N 1030, One Baylor Plaza, Houston, Texas 77030, USA
Nat Rev Immunol 11:685-92. 2011..In this Review, we summarize the current literature regarding the effects of infection on haematopoietic stem cell function and how these effects may have a pivotal role in directing the immune response from the bone marrow...
- mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert)Joseph T Rodgers
1 Paul F Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA 2 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
Nature 510:393-6. 2014....