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NIH Grants in April Support RNAi Work In Kidney Disease, Delivery, and Cancer

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A series of RNAi-related grants issued by the National Institutes of Health began this month, including one supporting research into the use of RNAi to treat kidney disease, one funding the development of new delivery vectors, and one that may help identify targets for cancer therapeutics.

The first grant, entitled "RNAi to Limit Kidney Ischemia/Reperfusion Injury," was issued to Harvard Medical School's Judy Lieberman. According to the grant's abstract, the project will study "specific applications of RNAi to protect the kidney from hypotoxic injury by silencing the Fas death receptor, and to investigate whether silencing FAS reduces inflammation or induces a non-specific interferon response."

Specifically, Lieberman is aiming to investigate the potential of modified siRNAs to silence Fas expression in the kidneys and provide protection from renal ischemia when delivered intravenously or through local catheterization, as well as to determine whether Fas silencing during renal ischemia modulates inflammatory and interferon responses in the kidney and systemically.

Lieberman has co-authored several papers on the in vivo use of siRNAs to target Fas, including one published late last year in the Proceedings of the National Academy of Sciences demonstrating that a hydrodynamic injection of siRNAs targeting Fas reduced Fas mRNA and protein expression in the kidneys of mice that had renal ischemia-reperfusion injury. The treated mice also experienced significant survival over controls.

The PNAS work was done in collaboration with Peter Hamar, an investigator at Semmelweis University in Hungary. The abstract notes that the grant project is designed to both help Lieberman's lab "become more adept in mouse surgical methods and physiology, and … provide the resources for … Hamar to perform the proposed experiments and broaden his research capability to master molecular and immunology methods."

The three-year grant was awarded by the Fogarty International Center, and is worth a total of $96,000.

The second grant, entitled "New Coding Vectors for microRNA and siRNA," was awarded to Kevin Ryan, a City College of New York researcher. According to the grant's abstract, Ryan is developing a new class of microRNA and siRNA delivery vectors with ribonuclease resistance that can be used for both genome research and therapeutics.

In the grant project, Ryan is looking to design, make, and study the utility of these vectors as a "genome exploration tool" in vitro and in cell culture, the abstract states. The study also aims "to evaluate [the] feasibility [of the technology] as a future gene therapy tool acting at the level of mRNA control."

Ryan's grant, which was awarded by the National Institute of General Medical Sciences, has a two-year term and is worth a total of $210,950.

The final grant, entitled "Making Hypomorphic Tumor Suppressors In Vivo Using RNAi," was issued to Cold Spring Harbor Laboratory investigator Scott Lowe. According to the grant's abstract, Lowe is looking to use RNAi to study tumor suppressor gene networks in vivo, in particular the impact of tumor suppressor hypomorphs on tumor development and responses to cancer therapy.

Lowe noted in the abstract that researchers at Cold Spring Harbor Lab have demonstrated that shRNAs can create "epi-allelic" series of hypomorphs that produce distinct tumor phenotypes in vivo. Additionally, Cold Spring Harbor Lab investigators have pioneered methods for using shRNAs to suppress gene function both in vivo and in vitro.

As such, the grant project's goals are to develop RNAi technology for suppressing gene function in both chimeric and germline settings; use conditional systems to determine the extent to which tumor suppressor gene inactiviation is required for tumor maintenance; and produce an epi-allelic series of tumor suppressor hypomorphs that may produce different pathologies depending on the level of suppression.

Additionally, the grant project will use newly available shRNA libraries capable of targeting cancer genes in the mouse genome to conduct unbiased genetic screens for modulators of tumor phenotypes, the abstract states. These screens are likely to be expanded to cover the entire genome, it adds.

"We expect these studies will provide new insights into how tumor suppressor networks are disabled during the development of particular neoplasias, and ultimately identify key nodes in these networks that may be sensitive to therapeutic intervention," the abstract notes. "Moreover, they will produce new mouse models of human cancer that can be used to understand treatment responses, and as preclinical models for testing novel therapies."

This grant, which was awarded by the National Cancer Institute, has a five-year term and is worth a total of $4.5 million.

— DM

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