Neuregulin(NRG) proteins have interesting, diverse biological properties, and offer opportunities to develop novel therapies. One of the long-term objectives of discovery research on NRG signalling is to identify potential clinical indications. Ultimately, recombinant human NRGs may be put to use as therapies. The overall goal of the proposed research is to discover potential therapeutic uses for a nrg-2 protein by following the strategy that was used for recombinant human glial growth factor 2(rhGGF2).That secreted isoform of nrg-1 was produced in mammalian cells, then used to explore responses in various biological systems. The work led to the discovery of nrg-1 functions and bioactivities that might be relevant to specific disorders, and thereby indicate potential therapeutic uses for rhGGF2. Now the focus is on identification of potential therapeutic uses for nrg-2. From preliminary work, human nrg-2 cDNAs were identified and used to construct an expression vector encoding a full-length, secreted human nrg-2 protein. Further, antisera and a standard bioassay have been developed to monitor expression and purification. Three Specific Aims are proposed in Phase 1 to demonstrate the feasibility of this approach. Aims 1 and 2 are directed at expressing and purifying moderate quantities of recombinant human nrg-2 protein to enable testing for specific bioactivities in selected in vitro assays (aim 3). PROPOSED COMMERCIAL APPLICATIONS: A large number of disorders of the nervous system still are without effective treatment. Recombinant human growth factors, due to their potent trophic and regenerative actions on damaged tissues, represent a novel approach to the discovery and development of drugs for treatment of neurological and degenerative disorders. Neuregulins are essential for normal development and have been shown to be efficacious in several animal models of disease. Thus NRGs present multiple opportunities to identify novel treatments for nervous system disorders. Accordingly, the commercial potential is large.
