The role BH3 and multi BH domain genes in regulating monocyte survival and functi

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DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease characterized by hyperplasia of the synovial lining, inflammation, and destruction of cartilage and bone. In RA, the balance between anti- and pro-apoptotic members of the Bcl-2 family may be shifted towards survival. We demonstrated that the anti-apoptotic proteins, Bcl-2 and Mcl-1 are increased while the pro-apoptotic protein Bim is decreased in RA synovial tissue as compared to controls. The study of deficiencies in anti-apoptotic members of the Bcl-2 family is complicated by embryonic lethality or early post-natal death. In contrast, mice deficient in pro-apoptotic Bcl-2 members such as Bak, Bax, or Bim survive and reach adulthood. Since Bim is a critical activator of apoptosis through sequestering Bcl-2/Mcl-1 and/or by activating Bak and Bax and since Bim is decreased in RA synovial tissue, Bim is a potential target for treatment of RA. We demonstrated that mice lacking the apoptotic initiator Bim but not the downstream effectors Bak or Bax develop a more severe form of inflammatory arthritis. This exacerbated disease in Bim-/- mice is associated with decreased apoptosis, increased expression of pro-inflammatory molecules, and more macrophages in pannus. Further, Bim-/- macrophages display elevated levels of IL-6, IL-1¿, and TNFa and enhanced expression of CD40 and CD69 in response to stimulation with LPS. Based on these data, we hypothesize that the ratio of Bim to Bcl-2 and/or Mcl- 1 serves as molecular rheostat that determines the extent of hyperplasia and activation of macrophages in the joint. We will use a pharmacological approach, a whole animal approach, and a cell-specific approach to identify how deficiency in Bim exacerbates inflammatory arthritis. These studies will potentially lead to novel therapeutic approaches to RA. The regulation of cell death and growth is vital for maintaining a balance in the human body. However, during the initiation and/or progression of the autoimmune disease, rheumatoid arthritis (RA), the balance is disrupted. In RA there is an increase in cellular growth and a concomitant decrease in cell death leading to an abnormal increase in the tissue that attaches to the cartilage/bone junction, the synovial lining. Analysis of tissue from joints of patients with RA revealed that the number of macrophages correlated with a worse prognosis. Monocytes (macrophage precursors) and macrophages are immune cells that produce the noxious factors in patients with RA and are responsible for removing dying cells or debris in tissues. We demonstrated that the death signaling cascade mediated by the pro-death protein Bim is dysfunctional in macrophages from patients with RA. Additionally, we have shown that mice lacking Bim in all cell types develop a worse form of arthritis and that the macrophages from these mice are highly activated, meaning they produce significant amounts of deleterious factors that exacerbate the inflammation. Therefore, our goal is to develop a therapeutic to activate the Bim death pathway and inhibit or induce remission in RA. Further our goal is to characterize mice lacking Bim or it signaling partners only in monocytes and macrophages.