This proposal outlines a 5-year career development plan for Ryan M. O'Connell, Ph.D., that begins with a 2 year mentored period and finishes with 3 years of independent research upon obtaining a tenure track position at an academic institution. The principal investigator (P.I.) has undergone 3 previous years of training as a postdoctoral scholar in the laboratory of David Baltimore, Ph.D., at the California Institute of Technology where significant research progress has been made in the field of miRNAs and the immune system. During the mentored phase of the proposed project, the P.I. will continue to work in Dr. Baltimore's laboratory and receive additional guidance in specific areas important for carrying out the proposed research agenda. The proposed work will next be completed during the independent period. The overall scientific goal of this proposal is to understand how mammalian hematopoiesis is regulated by microRNAs during inflammatory stress. This research direction is supported by compelling preliminary data, and the overwhelming medical need to understand how hematopoietic stress contributes to diseases such as cancer, anemia, immunodeficiency, and autoimmunity. The P.I. has previously identified a specific microRNA, miR-155, that is induced in the hematopoietic system during inflammation and sufficient to cause a myeloproliferative disorder upon its sustained expression in the hematopoietic system. Therefore, the central hypothesis to be tested is whether physiologically regulated miR-155 promotes myeloid expansion during inflammation, and does so by directly repressing SHIP1 and selecting specific C/EBP? protein isoforms to be expressed. Results will determine whether miRNAs regulate hematopoiesis during physiologically relevant inflammatory stress, and provide a mechanistic basis for this function. Furthermore, important insights will be gained regarding how miRNAs can serve as links between inflammation and hematological disorders.

Public Health Relevance

Promising advances in biomedical research indicate that both inflammation and microRNAs contribute to human diseases of hematological origins such as cancer, anemia and autoimmunity. This proposal will therefore examine the interplay between inflammation and miRNAs in the context of regulating hematopoiesis, and define a mechanistic basis for this novel function of miRNAs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL102228-04
Application #
8316418
Study Section
Special Emphasis Panel (NSS)
Program Officer
Welniak, Lisbeth A
Project Start
2011-08-10
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$207,887
Indirect Cost
$68,832
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kubinak, Jason L; Petersen, Charisse; Stephens, W Zac et al. (2015) MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 17:153-63
Lochhead, Robert B; Zachary, James F; Dalla Rosa, Luciana et al. (2015) Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis. PLoS One 10:e0135142
Kubinak, Jason L; Stephens, W Zac; Soto, Ray et al. (2015) MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun 6:8642
Zhao, Jimmy L; Ma, Chao; O'Connell, Ryan M et al. (2014) Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14:445-59
Hu, Ruozhen; Kagele, Dominique A; Huffaker, Thomas B et al. (2014) miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41:605-19
Zhao, Jimmy L; Rao, Dinesh S; O'Connell, Ryan M et al. (2013) MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. Elife 2:e00537
Hu, Ruozhen; Huffaker, Thomas B; Kagele, Dominique A et al. (2013) MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J Immunol 190:5972-80
O'Connell, Ryan M; Baltimore, David (2012) MicroRNAs and hematopoietic cell development. Curr Top Dev Biol 99:145-74
O'Connell, Ryan M; Rao, Dinesh S; Baltimore, David (2012) microRNA regulation of inflammatory responses. Annu Rev Immunol 30:295-312
Huffaker, Thomas B; Hu, Ruozhen; Runtsch, Marah C et al. (2012) Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep 2:1697-709