Rheumatoid arthritis (RA) is an autoimmune disease characterized by hyperplasia of the synovial lining, inflammation, and destruction of cartilage and bone. My laboratory has focused on the potential of activating the apoptotic cascade in RA as a potential therapeutic. In the Parent RO1, we have shown that in RA, the balance between anti- and pro-apoptotic members of the Bcl-2 family is shifted towards survival. Systemic delivery of a peptide corresponding to the death domain (BH3) of the apoptotic accelerator protein, Bim, using the non-specific TAT as a carrier, is successful in ameliorating inflammatory arthritis in mice. These studies together with the recent development of therapies that mimic the action of other pro-apoptotic proteins (BH3- mimetics) for cancer open a whole new avenue of therapy for RA. While these data are supportive of the therapeutic potential of the TAT-BH3 peptide, stabilization, localization, and targeted delivery of the peptide is required in order to understand the molecular mechanism of BH3 peptides. To overcome these issues we will utilize cutting-edge nanotechnology, which was not available at the time of the original submission of the parent RO1 as I was at Saint Louis University. Since Northwestern University is one of the leaders in nanotechnology, we established a collaboration with Dr. Mark Hersam (Department of Chemistry), an expert in single-walled carbon nanotubes. In addition, we have established a collaboration with Drs. Scott Budinger and Gokhan M. Mutlu (Division of Pulmonary and Critical Care), who already have shown that single-walled carbon nanotubes are not toxic to mice and that macrophages preferentially incorporate single-walled carbon nanotubes. Thus, we will use single walled carbon nanotubes as a novel and innovative delivery and tracking system for the BH3 peptides. Due to the inherent optical properties of single-walled carbon nanotubes, uptake, distribution, and localization of the nanotubes will be monitored by flow cytometry and by near infra-red whole body imaging. Since macrophages are one of the principal cell types responsible for the effector phase of RA and since the numbers of macrophages in the subsynovial lining are a biomarker for successful therapy, attaching the BH3 peptide to eliminate these cells has the potential to be an effective therapeutic. These studies will also be the first ever to demonstrate the therapeutic potential using single walled carbon nanotubes to deliver a cargo in RA. Moreover, the studies outlined in this proposal take advantage of new interactions among multi- and inter-disciplinary research teams at Northwestern University leading to novel therapies for RA.
Inflammatory diseases, including rheumatoid arthritis, are responsible for significant mortality and morbidity. Because treatments are often ineffective or must be discontinued due to side effects, a greater understanding of the mechanisms involved in the progression of disease is crucial to the development of more efficacious treatments. Our data suggest that enhancing apoptosis in effector cells may have significant therapeutic potential. Therefore, we will use nanotechnology to delivery apoptotic agonists to macrophages in order to identify, characterize, track, and inhibit their function.
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