Wegener's granulomatosis is a relapsing vasculitic disease of unknown etiology that carries a severe prognosis and responds poorly to current relatively toxic immunosuppressive therapy. Our working hypothesis is that there is an infectious agent(s) associated with induction or progression of Wegener's. We were funded via a supplement to RO1 AI39616 (HWV, investigator) to develop both degenerate primer PCR (Deg-PCR) and representation difference analysis (RDS) for purposes of pathogen discovery. We are now prepared to use these assays, and two additional methods, to seek candidate pathogens involved in human diseases. Key to this proposal, the combination or our expertise in molecular techniques and infectious diseases, and the clinical resources and protocols of the ongoing Wegener's Granulomatosis Etanercept Trial (WGET, Appendix A), provides a unique and unlikely to be duplicated opportunity to search for an infectious etiology of Wegener's granulomatosis. This proposal has four Aims. If candidate pathogens are identified, two contingent Aims will be pursued.
Aim 1) Identify candidate pathogen(s) associated with the induction or progression of Wegener's granulomatosis using culture on human fibroblasts;
Aim 2) Identify candidate pathogens(s) associated with the induction or progression of Wegener's granulomatosis using specific and degenerate PCR;
Aim 3) Identify candidate pathogen(s) associated with the induction or progression of Wegener's granulomatosis using representational difference analysis (RDA);
Aim 4) Identify candidate pathogen(s) associated with the induction or progression of Wegener's granulomatosis using inoculation of severely immunocompromised mice; Contingent Aim A) Development of assays for detecting candidate pathogen(s) associated with Wegener's granulomatosis; Contingent Aim B) Analyze the prevalence of infection in the patients taking part in the associated WGET trial, and control patients. We have assembled a team of co-investigators with expertise including clinical rheumatology, clinical trials, infectious disease, molecular biology, molecular pathogenesis, and statistics. The benefits of identifying potential etiologies for Wegener's are great, preliminary data shows that the methods are in hand, and the team assembled is well qualified to undertake the proposed studies.
| Karst, Stephanie M; Wobus, Christiane E; Lay, Margarita et al. (2003) STAT1-dependent innate immunity to a Norwalk-like virus. Science 299:1575-8 |
