We have learned a great deal recently about the mechanism and biology of a class of small non-coding RNAs called microRNAs. This remarkable class of RNAs constitute 2% of the genes in the human genome, and they repress the expression of protein-coding genes. This is achieved in animal specieis primarily by attenation of protein synthesis from mRNA transcripts which contain complementary sequence in their 3'untranslated regions. Although it is impossible yet to accurately estimate the extent of microRNA regulation, up to 30% of protein- coding genes are thought to be directly controlled by microRNAs. Genetic studies in model organisms support the notion that microRNAs play diverse roles in cell and organismal biology. We are interested in understanding the biological consequences of regulation by microRNAs. To this end, we have developed genetic and cell biological methods to study individual microRNAs in whole Drosophila tissues and cells. We will evaluate the mechanisms by which microRNAs buffer gene regulation against environmental perturbation such as temperature fluctuation. This is important for differentiation and development of the nervous system. The upstream regulatory pathways that regulate the process will be evaluated, and correlated to known biological functions of these pathways. We are also interested in the evolutionary implications of genetic buffering by microRNAs. We will experimentally test whether microRNAs buffer traits under selective pressure upon animal populations. Finally, we will evaluate the mechanisms by which microRNAs regulate cell morphogenesis in epithelial tissues, using a combination of quantitative experimental methods and theoretical physical modeling. The significance to health is manifold. The combined effects of microRNAs affect the expression of many human genes, and misregulation of microRNAs appear to underlie diverse disease phenomena such as cancer and virus infection.

Public Health Relevance

MicroRNAs are regulators of gene expression, and their dysfunction is linked to diverse forms of cancer. Additionally, microRNAs play important functions during infection by numerous viruses. This project is to understand how microRNAs control gene expression and their natural functions within the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077581-08
Application #
8520322
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Bender, Michael T
Project Start
2006-05-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$291,323
Indirect Cost
$75,860
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Posadas, Diana M; Carthew, Richard W (2014) MicroRNAs and their roles in developmental canalization. Curr Opin Genet Dev 27:1-6
Boisclair Lachance, Jean-Francois; Pelaez, Nicolas; Cassidy, Justin J et al. (2014) A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling. Dev Biol 385:263-78
Marques, Joao Trindade; Wang, Ji-Ping; Wang, Xiaohong et al. (2013) Functional specialization of the small interfering RNA pathway in response to virus infection. PLoS Pathog 9:e1003579
Cassidy, Justin J; Jha, Aashish R; Posadas, Diana M et al. (2013) miR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor. Cell 155:1556-67
Wu, Pei-Hsuan; Isaji, Mamiko; Carthew, Richard W (2013) Functionally diverse microRNA effector complexes are regulated by extracellular signaling. Mol Cell 52:113-23
Pelaez, Nicolas; Carthew, Richard W (2012) Biological robustness and the role of microRNAs: a network perspective. Curr Top Dev Biol 99:237-55
Gemp, Ian M; Carthew, Richard W; Hilgenfeldt, Sascha (2011) Cadherin-dependent cell morphology in an epithelium: constructing a quantitative dynamical model. PLoS Comput Biol 7:e1002115
Marques, Joao Trindade; Kim, Kevin; Wu, Pei-Hsuan et al. (2010) Loqs and R2D2 act sequentially in the siRNA pathway in Drosophila. Nat Struct Mol Biol 17:24-30
Carthew, Richard W; Sontheimer, Erik J (2009) Origins and Mechanisms of miRNAs and siRNAs. Cell 136:642-55
Lee, Young Sik; Pressman, Sigal; Andress, Arlise P et al. (2009) Silencing by small RNAs is linked to endosomal trafficking. Nat Cell Biol 11:1150-6

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