National Cancer Institute: Opportunity for a Cooperative Research and Development Agreement (CRADA) Collaboration in the Identification, Characterization and Development of Inhibitors of the Smad3 Signaling Protein for Use in the Treatment of Wounds and Fibrotic Diseases Characterized by Chronic Inflammation

The National Cancer Institute (NCI) seeks a Cooperative Research and Development Agreement (CRADA) Collaborator to aid NCI in the identification and development of inhibitors of the function of the Smad3 signaling protein. Smad3 and a closely related gene, Smad2, act as nuclear transcriptional activators in response to intracellular signals from the transforming growth factor betas (TGF-betas) and activin molecules (1,2). The existence of these genes was first proposed after a screen for developmental mutations in the nematode led to the identification of three genes, sma-2, sma-3, and sma-4, that were homologs of Drosophila MAD, a protein with a role in the signaling of a TGF-beta superfamily ligand (3). The Smad2 and Smad3 signaling pathways play important roles in the cellular proliferation, differentiation and migration crucial to cutaneous wound healing and the induction of fibrosis in diseases characterized by chronic inflammation (4). NCI has generated a line of mice that are homozygously deleted in the Smad3 gene (Smad3\ex8/ex8\ mice). These mice have made it possible for NCI to examine the contribution of Smad3 in cutaneous wound healing. Smad3\ex8/ex8\ mice survive into adulthood and show accelerated cutaneous wound healing characterized by an increased rate of re-epithelialization and a reduced local inflammatory infiltrate of monocytes and neutrophils. Thus, Smad3 appears to mediate in vivo signaling pathways that mediate key aspects of wound healing including influx of inflammatory cells and control of epithelial cell proliferation and migration. NCI's studies indicate that inhibitors of Smad3 function, such as specific, small molecule or antisense-related compounds, may accelerate cutaneous wound healing and may even be beneficial to other processes such as the treatment of extensive burns, the suppression of radiation-induced scarring, the growth of autologous skin grafts and the treatment of fibrotic diseases characterized by chronic inflammation. NCI is looking for a CRADA Collaborator with a demonstrated record of success in the isolation and characterization of small molecule protein inhibitors. The proposed term of the CRADA can be up to five (5) years.