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RNAi Grant Roundup

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Title: microRNAs as Targets for the Treatment of Hepatocellular Carcinoma

PI: Carlo Croce, Ohio State University

Term: Jan. 1, 2009 – Nov. 30, 2013

Amount Awarded to Date: $519,141

Having discovered miRNA expression signatures specific for hepatocellular carcinoma and metastatic disease, the investigator aims to "assess the role of alterations in several microRNAs in the pathogenesis of [hepatocellular carcinoma] to define microRNAs that are suitable targets for therapeutic intervention," according to the grant's abstract.

The effort will specifically focus on miR-181a/b, miR-21, miR-25, miR-221/222 and miR-155, which are over-expressed in the disease, and miR-145, miR-215, miR-125, miR-126, miR-192, miR-223, and miR-122a, which are down-regulated.

It has also been discovered that certain miRNAs "potentially target the 3' UTR of the maintenance and de novo DNA methyltransferases," the abstract notes. As such, whether the loss of these miRNAs triggers over-expression of DNMTs and silencing of tumor suppressor genes associated to hepatocellular carcinogenesis will be determined.

Concurrently, the 3' UTRs of the DNA methyltransferases DNMT1, DNMT3A, and 3B will be sequenced "to determine whether mutations in target sequences of microRNAs result in their up-regulation," it adds.


Title: A Systematic Analysis of miR-34 Function in C. elegans

PI: Molly Hammell, University of Massachusetts Medical School

Term: Jan. 1, 2009 – Dec. 31, 2010

Amount Awarded to Date: $54,842

In light of previous work demonstrating a role for miR-34 in oncogenesis and tumor suppression in vertebrates, the project will identify targets of the miRNA through computational, biochemical, and molecular techniques.

Since mir-34 has no family members in C. elegans, yet lacks an overt phenotype, the investigator will computationally identify and genetically validate microRNAs that cooperate to regulate mir-34 target genes, the abstract notes.


Title: Investigation of Notch-Inhibiting microRNAs in Glioma

PI: Benjamin Purow, University of Virginia, Charlottesville

Term:
Feb. 1, 2009 – Dec. 31, 2013

Amount Awarded to Date: $326,937

Having reported an oncogenic role for the Notch pathway in gliomas, the investigator will systematically examine two miRNA candidates, miR-7 and miR-326, as Notch-inhibiting tumor suppressors with therapeutic potential for the disease, according to the grant's abstract.

In the project, immunoblotting and 3'-UTR luciferase reporters will be used to validate which of the predicted Notch pathway members are indeed directly targeted by the miRNAs. Additionally, inhibitors of miR-7 and miR-326 will be examined for their ability to increase Notch activity and expression of Notch pathway targets.

Then, "expression of the various forms of these [miRNAs] will be quantified in human glioma and normal brain samples and their levels correlated to Notch activity and to levels of targeted Notch pathway proteins," the abstract notes. Later, "the phenotypic effects of transfecting miR-7 and miR-326 into established glioma lines will be evaluated and the contribution of Notch inhibition to these effects determined."

Lastly, the effects of miR-7 and miR-326 on growth, differentiation, and invasiveness in glioma tumor stem cell lines in vitro and in orthotopic xenograft mouse models will be determined.


Title: A System for Detecting Functional microRNA Targets

PI: Joan Elizabeth Davies, System Biosciences

Term: April 1, 2009 – March 31, 2010

Amount Awarded to Date: $180,703

The funded project will focus on developing and validating "a technology for matching known RNAs with corresponding inhibitory microRNAs," according to its abstract.

Specifically, the investigator aims to develop "a systematic tool to rapidly and routinely identify microRNAs that hybridize to any query RNA sequence" involving a puromycin-resistance reporter vector into which query RNA sequences can be introduced, and stably transduced cell populations that collectively over-express 550 different microRNAs but are comprised of individual cells over-expressing on average a single microRNA, the abstract adds.

"To use this system, reporter vectors containing target RNA sequences of interest are delivered into microRNA over-expressing cells by lentiviral infection," after which puromycin is added, the abstract notes. "Only individual cells that over-express a microRNA that hybridizes to the target RNA sequences will grow in the presence of puromycin. These puromycin resistant cells are then analyzed to determine the microRNA(s) that they express."


Title: Anti-Cancer RNA Nanoconjugates

PI: Robert Delong, Missouri State University

Term: April 1, 2009 – March 31, 2012

Amount Awarded to Date: $189,575

The project will focus on manufacturing and testing RNA-bound nanoparticles containing siRNAs or splice-site switching oligoribonucleotides targeted against the oncogene B-Raf to establish their utility as anti-cancer molecules, according to the grant's abstract.


Title: Double-Stranded RNA-Mediated Signaling Pathway and Gene Silencing

PI: Yi Liu, University of Texas Southwestern Medical Center

Term: April 1, 2009 – March 31, 2013

Amount Awarded to Date: $282,600

Based on previous work suggesting evolutionarily conserved roles of RNAi in gene silencing and defense mechanisms, as well as a novel link between RNAi pathway and DNA repair/replication processes, the project aims to determine the signaling pathway responsible for dsRNA-induced gene transcription, according to the grant's abstract.

Next, the investigator will "determine the biogenesis and function of the DNA damage-induced small RNA … [and] investigate the mechanism of aberrant RNA production after DNA damage.

"These proposed studies, using a combination of genetic, biochemical, and physiological approaches, will have important implications for the understanding of eukaryotic gene silencing and defense responses in general," it notes.


Title: Genetic Variants in microRNA-Related Genes and Skin Cancer Risk

PI: Hongmei Nan, Brigham and Women's Hospital

Term: April 1, 2009 – March. 31, 2011

Amount Awarded to Date:
$88,500

The project will "examine in detail the associations of genetic variants in microRNA-related genes with the risk of melanoma, squamous cell carcinoma, and basal cell carcinoma simultaneously," the abstract states.

In addition, the interactions between genetic variants in miRNA-related genes and constitutional host factors and UV exposure history on skin cancer risk, it adds.


Title: A RasGAP-microRNA Connection in Cardiac Hypertrophy

PI: Maha Abdellatif, University of Medicine and Dentistry, New Jersey

Term: April 15, 2009 – March. 31, 2014

Amount Awarded to Date: $390,000

In the project, the role of Ras GTPase-activating protein in regulating miR-1 during cardiac hypertrophy will be examined, according to the grant's abstract.

Preliminary data shows that RasGAP SH3-binding protein binds miR-1 in a RasGAP- and Akt-dependent manner. As such, the investigator and colleagues "hypothesize that hypertrophic stimuli induce Akt-mediated G3BP phosphorylation and its subsequent recruitment by RasGAP-filamin complex."

"This brings it into close proximity to miR-1, where it binds and hydrolyzes premature miR-1," the abstract notes. "Subsequently, down-regulation of miR-1 results in upregulation of its targets that include: RasGAP, Cdk9, fibronectin, endothelin, and insulin-like growth factor, among others."

The project specifically aims to study the mechanism of RasGAP-mediated down-regulation of miR-1 during myocyte hypertrophy, and examine the role of RasGAP and miR-1 during cardiac hypertrophy in a mouse model.


Title: Role of microRNA-499 in the Heart

PI: Joseph Shieh, University of California, San Francisco

Term: April 15, 2009 – March 31, 2014

Amount Awarded to Date: $125,415

The project will "address heart failure and the potential to alter heart failure by controlling the gene expression changes that characterize failure" based on a hypothesis that miRNAs play a key role in the condition, according to the grant's abstract.

In a mouse model, alteration of miR-499 levels was found to trigger characteristic gene expression patterns that are seen in heart failure, it adds. To further investigate this finding, the project will examine the expression patterns of miR-499 and specific myosin genes in the heart, determine whether miR-499 levels exacerbate heart failure in animal models of disease, and elucidate the pathway by which the miRNA exerts its putative regulatory role in heart failure.


Title: microRNA Function in the Development of the Cerebral Cortex

PI: Tao Sun, Weill Medical College of Cornell University

Term: April 23, 2009 – Feb. 28, 2014

Amount Awarded to Date: $421,875

The project will test the hypothesis that miRNAs maintain the neural progenitor pool and control neuronal production during cortical development.

To do so, mouse models in which miRNA biogenesis is temporally and spatially blocked in the cortex will be used to determine miRNA function in development of neural progenitors and postmitotic neurons, in cortical neuronal production, and anterior and posterior pattern formation, the grant's abstract states.

The project will also evaluate the roles of two specific miRNAs in neuronal production by altering their cortical expression levels, and examine the silencing effect of the miRNAs on potential target proteins during cortical development, the abstract adds.

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