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.

Public Health Relevance

During an infection, peripheral immune cells are consumed and must be replenished, ultimately through increased proliferation of hematopoietic stem cells (HSCs). We will use a mouse model of chronic Mycobacterium avium infection to understand changes in HSC function triggered by interferon-gamma signaling. Since some interferon-regulated genes are required for autophagy, we will examine the role of autophagy in the regulation of mouse and human HSCs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL098898-05
Application #
8617858
Study Section
Special Emphasis Panel (ZHL1-CSR-U (O1))
Program Officer
Welniak, Lisbeth A
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$130,508
Indirect Cost
$9,667
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Rodgers, Joseph T; King, Katherine Y; Brett, Jamie O et al. (2014) mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 510:393-6
Matatall, Katie A; Shen, Ching-Chieh; Challen, Grant A et al. (2014) Type II interferon promotes differentiation of myeloid-biased hematopoietic stem cells. Stem Cells 32:3023-30
King, Katherine Y; Baldridge, Megan T; Weksberg, David C et al. (2011) Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling. Blood 118:1525-33
Baldridge, Megan T; King, Katherine Y; Boles, Nathan C et al. (2010) Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 465:793-7