MicroRNAs (miRNAs) commonly repress gene expression by binding to the 3'untranslated region of target mRNAs, and thousands of mRNAs have been predicted to be targets of hundreds of miRNAs in animals. Despite intense studies in the past decade, the majority of regulatory miRNA::mRNA interactions for a broad spectrum of physiological functions remain to be elucidated. In C. elegans, genetic analyses have only linked a small percentage of miRNAs or miRNA families to prominent roles in development. The difficulty encountered in functional studies of miRNAs may be attributed in part to that multiple miRNAs from different families may collaborate to regulate a set of target genes for specific physiological functions. We may also hypothesize that a large number of miRNAs may function in cellular processes involved in animals'responses to environmental changes such as nutrient availability, stress conditions and pathogen infection. Our goal is to gain a global view of dynamic miRNA::target interactions in different tissues and under different physiological conditions to obtain insights regarding miRNA-mediated functions in stress and infection responses. We propose to combine novel systematic approaches with individual gene- based analysis to tackle the problem, using the nematode C. elegans as a model system. We will first evaluate physiological functions of miRNAs by disrupting activities of all miRNAs in selected tissues and examine the developmental and non- developmental consequences, including responses to stresses and infections. We will then identify and analyze miRNA::target interactions in selected tissues during development by applying AIN-2 immunoprecipitation, high-throughput RNA analysis, and computational methods. This approach will further be used to identify dynamic miRNA::target interactions during animals'responses to food deprivation, pathogen infection and other stresses. Finally, we will carry out experiments to verify miRNA::target interactions for selected pairs and analyze their functions in stress and pathogen responses. The results of this study should provide important insights regarding important functions of miRNA regulations and mechanisms of animals'defense against environmental stresses and infections.

Public Health Relevance

microRNAs are evolutionarily conserved small, non-coding RNAs that have been shown to play critical roles in a broad aspect of cellular and developmental processes, including many human diseases such as cancers, cardiac and neurological diseases, as well as animal's responses to various stresses. Research under this grant is expected to make a solid contribution by providing new insights into miRNA functions in stress responses and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047869-19
Application #
8331483
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
1992-08-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
19
Fiscal Year
2012
Total Cost
$293,395
Indirect Cost
$93,395
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Than, Minh T; Kudlow, Brian A; Han, Min (2013) Functional analysis of neuronal microRNAs in Caenorhabditis elegans dauer formation by combinational genetics and Neuronal miRISC immunoprecipitation. PLoS Genet 9:e1003592
Kudlow, Brian A; Zhang, Liang; Han, Min (2012) Systematic analysis of tissue-restricted miRISCs reveals a broad role for microRNAs in suppressing basal activity of the C. elegans pathogen response. Mol Cell 46:530-41
Zhang, Liang; Ding, Lei; Cheung, Tom H et al. (2007) Systematic identification of C. elegans miRISC proteins, miRNAs, and mRNA targets by their interactions with GW182 proteins AIN-1 and AIN-2. Mol Cell 28:598-613
Cui, Mingxue; Han, Min (2003) Cis regulatory requirements for vulval cell-specific expression of the Caenorhabditis elegans fibroblast growth factor gene egl-17. Dev Biol 257:104-16
Chen, Z; Han, M (2001) C. elegans Rb, NuRD, and Ras regulate lin-39-mediated cell fusion during vulval fate specification. Curr Biol 11:1874-9
Chen, Z; Han, M (2001) Role of C. elegans lin-40 MTA in vulval fate specification and morphogenesis. Development 128:4911-21
Sundaram, M; Han, M (1996) Control and integration of cell signaling pathways during C. elegans vulval development. Bioessays 18:473-80
Sundaram, M; Yochem, J; Han, M (1996) A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in Caenorhabditis elegans. Development 122:2823-33
Sundaram, M; Han, M (1995) The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83:889-901

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