The inflammatory response is one of the body's most important defenses against infection. One initiator of inflammation is bacterial lipopolysaccharide (LPS). We found some years ago that LPS will induce in macrophages 3 microRNAs. These are small RNAs that can have huge regulatory influences on protein levels. We have therefore been characterizing these 3 RNAs from various points of view and this request is for funds to study these RNAs in depth. One of the microRNAs has been linked to cancer induction and may provide a link between inflammation and cancer. We have also included plans to study another microRNA family because of its potential relationship to immune cell maturation. The planned studies take advantage of today's ability to manipulate the genetics of mice. Thus, overexpression and knockout studies will allow us to examine the consequences to mouse physiology of too much or none of the particular microRNAs. The overexpression studies will be done by incorporating into viral vectors genes that express the microRNAs, infecting bone marrow stem cells with these vectors and transferring the infected cells to lethally irradiated host mice. We will use high resolution surface marker analysis to characterize the role of these microRNAs in the generation and behavior of particular subsets of immune cells. In this work, we will also use in vitro expression in cells through vectored delivery of genes to the cells. MicroRNAs are processed from precursors and we have found that the processing itself is regulated. We plan to examine how this regulation is achieved. To understand how these microRNAs work we will characterize the target genes that they regulate. This involves bioformatics to find candidates, determining the genes whose expression is sensitive to a particular microRNA and then study of the role of those genes. For the microRNA family that may be involved in immune cell development, we suspect that it could be controlling the final stage of differentiation of the cells that make antibodies. We will therefore concentrate on examining that stage of immune cell development with an emphasis on the possible role of a protein usually associated with protecting the genome, p53.

Public Health Relevance

Scientists have long thought that the immune system is controlled by proteins. Our recent work has implicated some small RNA molecules as controllers of inflammatory and immune responses. We plan to examine how such RNAs might work with an emphasis on the relationship between cancer and inflammation. Microbial infections and cancer are among the leading causes of human diseases worldwide. Therefore, it is imperative that we continue to define the molecular basis underlying these devastating problems. Very recently, micro-RNAs have emerged as a novel class of gene expression regulators that are implicated in both immune system regulation and cancer biology. Our group has found that a small number of miRNAs are potently induced by the innate immune response to infection, and therefore propose to characterize the roles of these miRNAs in host defense against infection and tumorigenesis

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-III-B (09))
Program Officer
Palker, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
California Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
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
So, Alex Yick-Lun; Sookram, Reeshelle; Chaudhuri, Aadel A et al. (2014) Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias. Blood 124:1502-12
So, Alex Yick-Lun; Zhao, Jimmy L; Baltimore, David (2013) The Yin and Yang of microRNAs: leukemia and immunity. Immunol Rev 253:129-45
O'Connell, Ryan M; Baltimore, David (2012) MicroRNAs and hematopoietic cell development. Curr Top Dev Biol 99:145-74
Chaudhuri, Aadel A; So, Alex Yick-Lun; Mehta, Arnav et al. (2012) Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proc Natl Acad Sci U S A 109:4233-8
O'Connell, Ryan M; Rao, Dinesh S; Baltimore, David (2012) microRNA regulation of inflammatory responses. Annu Rev Immunol 30:295-312
Chaudhuri, Aadel A; So, Alex Yick-Lun; Sinha, Nikita et al. (2011) MicroRNA-125b potentiates macrophage activation. J Immunol 187:5062-8
Boldin, Mark P; Taganov, Konstantin D; Rao, Dinesh S et al. (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208:1189-201
Zhao, Jimmy L; Rao, Dinesh S; Boldin, Mark P et al. (2011) NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A 108:9184-9
O'Connell, Ryan M; Chaudhuri, Aadel A; Rao, Dinesh S et al. (2010) MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc Natl Acad Sci U S A 107:14235-40

Showing the most recent 10 out of 13 publications