The goal of this project is to understand how inflammatory signaling through toll like receptor 2 (TLR2) regulates both normal and premalignant hematopoietic stem cells (HSCs). TLR2 is a member of the TLR family of pattern-recognition receptors that play a central role in the innate immune response. Studies of TLRs have largely focused on mature immune cell populations, however TLRs are also expressed on HSCs, and recent reports demonstrate that TLR signaling may influence the immune response from the level of the HSC. Furthermore, deregulated TLR signaling, and in particular increased TLR2 expression and signaling, is associated with myelodysplastic syndromes (MDS), a group of HSC disorders characterized by ineffective hematopoiesis and a high risk of transformation to acute leukemia. Thus, aberrant TLR2 signaling may have clinically significant detrimental effects on HSCs. Our preliminary data suggest that TLR2 signals influence HSC numbers, mobilization and function. Using chimeric mouse studies, we determined that these effects of TLR2 signaling on HSCs are mediated by both cell autonomous and cell non-autonomous mechanisms. We therefore hypothesize that TLR2 signaling from multiple cell types contributes to the regulation of HSCs, and TLR2-induced changes in HSC function may contribute to the pathogenesis of MDS. In this proposal we will use CyTOF mass cytometry and conditional knockout mouse studies to identify the cell types in which TLR2 signaling is enhanced in MDS and determine the effects of conditional loss of TLR2 signaling from different hematopoietic and stromal cells types to the regulation of HSCs. In addition, we will use a mouse model of MDS in which we either augment or reduce TLR2 signaling to test the hypothesis that enhanced TLR2 signaling contributes to the pathogenesis of this disease. These studies will further our understanding of how TLR2 regulates HSCs and test it's utility as a therapeutic target in MDS. More broadly, we hope to gain a better understanding of how TLR signals regulate both normal and premalignant HSCs, and we anticipate that these studies will have implications not only for the pathogenesis of MDS, but for how aberrant TLR signaling (e.g., chronic infection) may contribute to other cases of bone marrow failure and/or leukemogenesis. Future studies will build upon these results and focus on the downstream mediators of the effects of TLR2 signaling on HSCs, with the goal of identifying genes that contribute to HSC cycling, differentiation, mobilization and/or loss of function in response to TLR signals.

Public Health Relevance

Toll like receptor 2 (TLR2) is a member of the TLR family of pattern recognition receptors that are important for pathogen recognition and innate immunity. Recent studies suggest that TLR2 signaling may regulate hematopoietic stem cells (HSCs), and enhanced TLR2 signaling is associated with the myelodysplastic syndromes, a group of HSC disorders characterized by cytopenias and a high risk of transformation to acute leukemia. In this project, we are testing the role of TLR2 signaling from different cell types in the bone marrow to the regulation of HSCs, and determining the contribution of TLR2 signaling to the pathogenesis of MDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134896-02
Application #
9402647
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Thomas, John
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130