Tumor necrosis factor-alpha (TNF-alpha) is pivotal in triggering the immune system to produce proinflammatory cytokines in response to a variety of insults to the cell. However, data suggests that many symptoms of disease are a result of toxic effects of the proinflammatory cytokines rather than the initial insult. The most advanced programs, using monoclonal antibodies to reduce TNF-alpha activity, have reported disappointing results. Given the vast number of disease states in which TNF-alpha is involved, there is ample opportunity for the development of therapeutics which both up- and down-regulate TNF-alpha production. Message is developing drugs which target RNA-protein interactions as a means of modulating protein production. The TNF-alpha mRNA contains A+U-rich sequences thought to be involved in destabilization of the mRNA through an interaction with specific A+U-rich RNA binding proteins. The goal of this Phase I proposal is to clearly define these interactions at the molecular level to generate the necessary reagents for a drug screening program in Phase II, and also to enable the generation of a model of the interaction that will be used in the design of directed small molecule libraries against the TNF-alpha mRNA.
The potential commercial application of the research proposed in this grant is the development of therapies targeting TNF-alpha that will be applicable to a variety of pathophysiological conditions. Moreover, the technology developed in identifying such a compound has commercial value of its own for the development of proprietary screening assays that can be licensed to other companies.
