Calcipressins: Lead Targets for Autoimmune, Inflammatory, and Cardiovascular Disease
Summary The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. Researchers at Harvard University have discovered a novel group of endogenous inhibitors that competitively inhibit the activity of calcineurin. This discovery has important implications for the development of next-generation immunosuppressive agents that mitigate the side effects associated with current treatments.
A novel family of endogenous calcineurin inhibitors, termed calcipressins (Csp), which modulate the pattern of calcineurin-dependent transcription. Csp1-deficient mice showed abnormalities in lymphocyte development, had higher endogenous amounts of calcineurin, and underwent premature cell death in comparison to wild-type cells expressing Csp1. Additionally, a Csp1 peptide binds competitively to calcineurin and inhibits NFAT localization to the nucleus.
Applications Applications: The development of next-generation compounds for the treatment of the inflammatory response, such as those related to autoimmunity and organ transplant rejection.
Publications and Patents:
Ryeom S, Greenwald RJ, Sharpe AH, McKeon F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nat Immunol. 2003 Sep;4(9):874-81.
Chan B, Greenan G, McKeon F, Ellenberger T. Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13075-80.
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McKeon, Frank D
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