Research in my laboratory has made critical findings related to the molecular, cellular, and genetic basis of Myelodysplastic Syndromes (MDS), a complex and poorly understood hematopoietic stem cell (HSC) failure syndrome. The complexity and heterogeneity of MDS, and the lack of mouse models, remain as major obstacles to understanding and effectively treating this disease. A major focus of my lab has been the intersection of immune biology and MDS. Namely, we have uncovered and characterized genetically-driven aberrant activation of the Toll- like receptor (TLR) (i.e., innate immune) pathway in MDS HSC, and now have evidence that TLR signaling is a major unifying driver of MDS pathogenesis. While dissecting the role of TLR signaling in MDS HSC, we identified a critical function of TLR signaling in normal HSC, a finding that has broader implications in chronic immune-related disorders and hematopoietic processes. As such, my research program has developed transformative and innovative approaches to investigate the intersection of TLR signaling, hematopoiesis, and MDS, which serve as the foundation for this proposal: (i) to dissect the genetic, molecular, and cellular underpinnings of MDS, with an emphasis on genetically-driven activation of TLR signaling (Research Focus 1); (ii) to evaluate the developmental requirement of the TLR signaling hub, TRAF6, in normal HSC function and MDS (Research Focus 2); and, (iii) to use the knowledge gained by our basic research to identify and develop novel therapeutic modalities for the treatment of MDS (Research Focus 3). The proposed research will impact our understanding of the initiation, progression, and treatment of MDS.

Public Health Relevance

Myelodysplastic syndromes (MDS) are a collection of acquired or inherited diseases wherein the bone marrow produces too few blood cells, and patients progress to acute leukemia. We idenitified that aberrant activation of the Toll-like receptor (TLR) pathway is a unifying driver of MDS pathogenesis. Research initiatives to dissect the genetic, molecular, and cellular underpinnings of MDS, with an emphasis on chronic activation of TLR signaling, will be pursued; namely, to evaluate the developmental requirement of the TLR signaling in normal HSC function and MDS, and to use the knowledge gained by our basic research to identify and develop novel therapeutic modalities for the treatment of MDS

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL135787-02
Application #
9411762
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
El Kassar, Nahed
Project Start
2017-01-10
Project End
2023-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Niederkorn, Madeline; Starczynowski, Daniel T (2017) GMP-ing to Spatial Conclusions about Emergency and Leukemic Myelopoiesis. Cell Stem Cell 20:579-581
Varney, M E; Choi, K; Bolanos, L et al. (2017) Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia 31:1659
Fang, Jing; Bolanos, Lyndsey C; Choi, Kwangmin et al. (2017) Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol 18:236-245
Varney, M E; Choi, K; Bolanos, L et al. (2017) Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia 31:491-495