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

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079243-05
Application #
8260519
Study Section
Special Emphasis Panel (ZRG1-III-B (09))
Program Officer
Palker, Thomas J
Project Start
2008-05-15
Project End
2013-11-30
Budget Start
2012-05-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$393,265
Indirect Cost
$148,240
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Jiang, Shuai; Baltimore, David (2016) RNA-binding protein Lin28 in cancer and immunity. Cancer Lett 375:108-13
Mehta, Arnav; Zhao, Jimmy L; Sinha, Nikita et al. (2015) The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression. Immunity 42:1021-32
Mehta, Arnav; Mann, Mati; Zhao, Jimmy L et al. (2015) The microRNA-212/132 cluster regulates B cell development by targeting Sox4. J Exp Med 212:1679-92
Zhao, Jimmy L; Baltimore, David (2015) Regulation of stress-induced hematopoiesis. Curr Opin Hematol 22:286-92
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
Okoye, Isobel S; Czieso, Stephanie; Ktistaki, Eleni et al. (2014) Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity. Proc Natl Acad Sci U S A 111:E3081-90
So, Alex Yick-Lun; Zhao, Jimmy L; Baltimore, David (2013) The Yin and Yang of microRNAs: leukemia and immunity. Immunol Rev 253:129-45
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
Cheng, Henry S; Sivachandran, Nirojini; Lau, Andrew et al. (2013) MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med 5:1017-34

Showing the most recent 10 out of 22 publications