The recent discoveries of microRNAs (miRNAs), RNA interference, short interfering RNAs, and small modulatory RNAs have revealed potentially widespread gene regulatory mechanisms that are mediated by short RNAs in animal and plant development. miRNAs are an abundant class of~22 nt endogenous noncoding RNAs. Some have been shown to play an important role in plant and animal development by controlling gene expression at the posttranscriptional level. Recently it was demonstrated that miR-181 could promote B-cell differentiation in vitro and in vivo, providing the first evidence that miRNAs have regulatory roles in vertebrate development (Chen et al., Science, 2004, 303:83). However, examples of miRNAs functioning in vertebrate development are still rare, and the molecular mechanisms through which miRNAs exert their functions are largely unclear. This research proposal addresses these fundamental questions and aims to establish the potential widespread influences of miRNA-mediated posttranscriptional gene regulatory circuitries during hematopoiesis. Through miRNA cloning and expression analyses, we have identified a set of hematopoietic miRNAs that may play important roles in lineage differentiation. We will try to define the functions of these miRNAs in various aspects of hematopoietic lineage differentiation so that we can establish broader roles for miRNAs in hematopoiesis (aim 1). With defined in vitro and in vivo differentiation assays we will be able to dissect the potential signaling pathways that are regulated by miRNAs, determine the structural and functional relationships of miRNA genes, define the progenitor cell population(s) that miRNAs act on, and delineate the cellular processes controlled by miRNAs (aim 2). Finally, we will combine computational and experimental approaches to identify the functionally relevant target genes of hematopoietic miRNAs (aim 3). Understanding the biological functions of miRNAs in hematopoiesis will shed light on the roles of miRNAs in hematological disorders and could lead to novel therapeutic strategies to correct many hematological disorders, including leukemias. The proposed research will also provide methods, insights, and inspiration to those seeking to place miRNAs into other biological processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL081612-01
Application #
6964041
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Di Fronzo, Nancy L
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$398,690
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Fragoso, Rita; Mao, Tin; Wang, Song et al. (2012) Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1. PLoS Genet 8:e1002855
Kluiver, J L; Chen, C-Z (2012) MicroRNAs regulate B-cell receptor signaling-induced apoptosis. Genes Immun 13:239-44
Arnold, Christopher P; Tan, Ruoying; Zhou, Baiyu et al. (2011) MicroRNA programs in normal and aberrant stem and progenitor cells. Genome Res 21:798-810
Yue, Si-Biao; Trujillo, Robin Deis; Tang, Yujie et al. (2011) Loop nucleotides control primary and mature miRNA function in target recognition and repression. RNA Biol 8:1115-23
Trujillo, Robin Deis; Yue, Si-Biao; Tang, Yujie et al. (2010) The potential functions of primary microRNAs in target recognition and repression. EMBO J 29:3272-85
Wong, Piu; Iwasaki, Masayuki; Somervaille, Tim C P et al. (2010) The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Cancer Res 70:3833-42
Basso, Katia; Sumazin, Pavel; Morozov, Pavel et al. (2009) Identification of the human mature B cell miRNome. Immunity 30:744-52
Lodish, Harvey F; Zhou, Beiyan; Liu, Gwen et al. (2008) Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8:120-30
Kuhnert, Frank; Mancuso, Michael R; Hampton, Jessica et al. (2008) Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development 135:3989-93
Liu, Gwen; Min, Hyeyoung; Yue, Sibiao et al. (2008) Pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in early T cell development. PLoS One 3:e3592

Showing the most recent 10 out of 12 publications