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NIH Issues Four RNAi-Related Grants in February

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February proved to be a popular month for RNA interference-related grants, with the National Institutes of Health providing four US researchers with more than $850,000 to fund their work through 2005.

The first grant was awarded to Rockefeller University researcher Matthew Poy by the National Institute of Diabetes and Digestive and Kidney Diseases for his research into the role of microRNAs in pancreatic islet function.

Poy’s grant runs between Feb. 1, 2005, and Jan. 31, 2008. The NIDDK has earmarked $48,296 for his research in 2005.

According to the grant’s abstract, Poy and his colleagues have identified novel miRNAs that are specific to the pancreatic islet, and are conserved in the mice and humans, suggesting a role in endocrine pancreas specification and glucose-induced secretion.

Poy recently co-authored a Nature paper in which he described the cloning and identification of miR-375, an miRNA that suppresses glucose-induced insulin secretion when over-expressed.

Under the NIDDK grant project, Poy is planning to over-express two novel islet-specific miRNAs in pancreatic beta cell lines and islets in order to study insulin secretion in response to a variety of insulin secretagogues, the abstract states.

The researchers are also planning to inhibit the function of the miRNAs by transfecting 2’-O-methyl RNA oligos complementary to the islet-specific miRNAs, and to generate a mutant mouse in which the most abundant islet-specific miRNAs have been replaced with a gene encoding a red fluorescent protein.

The second miRNA-related grant was awarded to Daniel Boden of the Aaron Diamond AIDS Research Center by the National Institute of Allergy and Infectious Diseases. The grant is supporting Boden’s research into the use of a natural miRNA cluster, expressing miR-35 to miR-41, to combat HIV.

Boden’s grant is set to run between Feb. 1, 2005, and Jan. 31, 2007. He has been awarded $271,563 in funding for the first year of the grant.

In the grant’s abstract, Boden notes that he and his colleagues have demonstrated the emergence and selection of HIV quasi-species resistant to siRNA targeting the viral transactivator protein tat.

“To counteract the rapid emergence of resistance, we hypothesize that co-expression of multiple siRNAs targeting conserved viral RNA sequences, as well as mRNA sequences of critical host genes, may reduce the emergence of siRNA-resistant virus,” Boden noted in the abstract.

Under the grant project, the researcher aims to use DNA vectors, expressing multiple siRNAs against HIV RNA and co-receptor CCR5 and delivered by the microRNA cluster, to achieve intracellular anti-retroviral immunity in stable cell lines and primary lymphocytes.

The National Institute of General Medical Sciences awarded Washington University’s Sarah Elgin a four-year grant for her work examining RNAi-directed assembly of heterochromatin in Drosophila.

Elgin’s project is set to run between Feb. 1, 2005, and Jan. 31, 2009. She has been awarded $313,650 for the first year of the effort.

Elgin noted in the grant’s abstract that “genes normally present in euchromatic domains are silenced when packaged into heterochromatin,” and that “loss-of-function mutations that result in a loss of silencing have identified many critical components of heterochromatin.

“Heterochromatin formation in pericentric regions appears to be dependent on histone deacetylation, followed by methylation of histone H3 at lysine 9 to generate H3-mK9, and association of heterochromatin Proteins 1 and 2,” she stated.

Elgin stated that the silencing of transgenes embedded in heterochromatin is lost due to mutations in piwi, aubergine, or homeless (spindle-E), all of which encode RNAi components, and that a mutation of homeless leads to a reduction in H3-mK9, and a dramatic delocalization of HP1.

Elgin hypothesizes that a targeting complex containing siRNAs homologous to repetitious elements in heterochromatin can direct specific association of HP1 with these regions. She intends to validate this model by testing candidate loci for loss-of-function mutations that produce the aforementioned phenotypes and identifying other RNAi components and histone-modification enzymes involved; by using a Tap-tag approach to isolate protein complexes associated with three proteins — homeless, a Paz/Piwi domain protein, and SDS3 — to determine patterns of interaction; and by developing an assay for the resultant phenotypes in tissue culture cells to help screen for critical factors.

Lastly, Northwestern University researcher Erik Sontheimer has received a grant from the NIGMS to study RNA silencing complex assembly and function.

According to the grant’s abstract, the project aims to determine the biochemical pathway of RISC assembly and function using Drosophila embryo lysates that are active for RNAi in vitro.

Sontheimer’s grant has a term running between Feb. 1, 2005, and Jan. 31, 2009. He has been awarded $231,987 for the first year.

Drosophila RISCs of differing sizes have been reported, but the relationships between them are unclear, and almost nothing is known about how they assemble,” Sontheimer stated in the abstract. “Furthermore, the identity of the siRNA-directed endonuclease remains unknown.

“We have developed a novel native gel electrophoresis assay that we can use to monitor protein complexes that form on radiolabeled siRNA [and] … have used this assay to identify at least three complexes, two of which (called R1 and R2) are intermediates in a RISC assembly pathway,” he noted. “The other complex, R3, is a very large and potentially ribosome-associated form of RISC that can specifically recognize and cleave targeted mRNAs.”

Under the grant project, Sontheimer plans to characterize the intermediate complexes and determine the requirements for their assembly into higher-order silencing complexes. He also intends to purify the R3 complex to identify proteins present within it, and use site-specific photocrosslinking to identify RISC components that contact functionally distinct regions of the target mRNA during RISC assembly, activation, and function.

— DM

 

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