Richard Pope, MD
Chief, Department of Medicine, Division of Rheumatology
Mabel Greene Myers Professor of Medicine -- Rheumatology
Feinberg School of Medicine
Our laboratory has focused on two areas. First, is the evaluation of the regulation of TNFa in macrophages and the development of a gene therapy approach to suppress the expression of TNFa. These studies have resulted in characterization of the transcription factor C/EBPb in RA synovial tissue. Further we have characterized the mechanism of regulation of TNFa gene expression in macrophages by C/EBPb, c-Jun and NF-kB. Replication defective adenoviral vectors expressing dominant negative or inhibitory versions of each of these transcription factors have been utilized to characterize the regulation of the expression of the TNFa gene in macrophages. Additionally, we have developed replication defective adenoviral vectors that express TNFa antisense and ribozyme molecules. These molecules specifically inhibit TNFa gene expression. Many of these vectors are currently being examined in an experimental model of RA called adjuvant induced arthritis.
The second area of interest relates to apoptosis or programmed cell death. A potential role for induction of apoptosis as a therapeutic approach in autoimmune diseases, including RA, has been proposed. Therefore we are examining the mechanisms that protect macrophages and FLS from apoptosis. . We recently identified the upregulation of the anti-apoptotic protein, Flice Like Inhibitory Protein (Flip), during monocyte to macrophage differentiation. We have demonstrated that Flip is responsible for protecting macrophages from Fas-mediated apoptosis. Additionally we have shown that inhibition of NF-kB results in macrophage apoptosis. This is mediated by causing damage to the mitochondria, which results in cytochrome c release, activation of caspase 9 and cell death by apoptosis. Cell death is protected in macrophages by the expression of Bcl-xL and Akt-1.
We are currently examining these hypotheses: (1) that the regulated expression of Flip controls Fas-mediated apoptosis in macrophages; (2) that the constitutive activation of NF-kB protects macrophages from apoptosis, which is initiated by loss of mitochondrial transmembrane potential (Dym), and that this NF-kB activation is mediated by Akt-1 and (3) that Flip is expressed in RA synovial macrophages and that inhibition of Flip or NF-kB activation will lead to apoptosis. Additional studies have demonstrated that inhibition of Bcl-2 by a replication defective adenoviral vector that reduced Bcl-2 resulted in apoptosis also mediated by cytochrome c release, caspase 9 activation and cell death by apoptosis.