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Our laboratory employs state-of-the-art cell culture and animal models to pursue multi-disciplinary projects spanning microbiology, immunology, genetics, cell biology, and neuroscience. The essence of our work is bacterial pathogenesis in the second-most common infectious disease and neuro-immune interactions in a crippling pain syndrome. A key to our success is the rich training environment resulting from the close collaboration between clinical and basic scientists.
Urinary tract infection (UTI) is both a major medical issue and a fascinating problem of bacterial pathogenesis. Our UTI studies involve all aspects of host pathogen interactions - from the immediate biochemical signaling evoked in bladder cells, to the associated inflammation, to the development of adaptive immune responses. We recently identified a novel signaling response of bladder cells induced by binding of uropathogenic E. coli (UPEC), and we showed that this signaling event mediates the mutually-exclusive processes of epithelial cell apoptosis and bacterial invasion of bladder epithelial cells. How a single initiating signal that occurs within seconds can mediate these disparate cellular responses is an active area of study. At the other end of the temporal spectrum, we have identified a candidate live-attenuated UTI vaccine based on a UPEC mutant. We find that the UPEC mutant vaccine induces protective responses 100-fold greater than wild type UPEC. We are now determining the mechanism of this enhanced response by testing the hypothesis that the UPEC mutant skews the normal immune response and thus generates a more effective immunity.
Although pelvic pain can result from acute infection, as in UTI, some diseases are associated with devastating, chronic pelvic pain. Interstitial cystitis (IC) is a debilitating chronic pelvic pain syndrome of unknown origin that is often considered a chronic bladder inflammation. We utilize a herpesvirus to induce an IC-like condition in mice. Using this neuro-immune mouse IC model, we have identified the mechanisms that result in both bladder pathophysiology and pelvic pain. Interestingly, while both pain and bladder damage require mast cell activation, these effects are separable in a manner consistent with the human disease. Pelvic pain results from the release of mast cell histamine, but bladder pathology is driven by mast cell release of tumor necrosis alpha (TNF). Current studies include the genetic basis of pain susceptibility, the spinal regulation of histamine and TNF release, and the viral basis of pain. In addition, we recently were awarded a prestigious NIH center grant to study pelvic pain syndromes. The center award will extend our bladder pelvic pain studies to prostate- and bowel-associated pelvic pain and determine the mechanisms of pelvic organ crosstalk and signal integration in the spinal cord in mice. In complementary studies, our center collaborators will examine cortical and cognitive changes in pelvic pain patients using a combination of functional MRI and behavioral tests. Other center collaborators are developing novel quality-of-life tests to characterize pelvic pain non-invasively within populations. Thus, this center will illuminate pelvic pain mechanisms in clinical, epidemiologic, and basic animal studies.
Selected Publications:
Billips, B.K., Cashy, J.P., Schaeffer, A.J., and D.J. Klumpp. 2009. A live-attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli. The Journal of Infectious Diseases 2009: 263-272.
Thumbikat, P., Berry, R.E., Zhou, G., Billips, B.K., Yaggie, R.E., Zaichuk, T., Sun, T-T., Schaeffer, A.J., and D.J. Klumpp. 2009. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathogens 5:e1000415 (PMCID: PMC2669708).
Berry, R.E, Klumpp, D.J., and A.J. Schaeffer. 2009. Urothelial cultures support intracellular-bacterial community formation by uropathogenic Escherichia coli. Infection & Immunity 7: 2762-2772.
Klumpp, D.J. and C.N. Rudick. 2008. A summation model of pelvic pain in IC/PBS. Nature Clinical Practice Urology 9: 494-500.
Rudick, C.N., Bryce, P.J., Guichelaar, L.A., Berry, R.E., and D.J. Klumpp. 2008. Mast cell-derived histamine mediates cystitis pain. PLoS ONE 3(5): e2096. doi:10.1371/journal.pone.0002096 (PMCID: PMC2346452).
Chen, M.C., Keshavan, P., Gregory, G.D., and D.J. Klumpp. 2007. RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis. American Journal of Physiology–Renal Physiology 292: F1372-F1379.
Billips, B.K., Forrestal, S.G., Johnson, J.R., Klumpp, D.J., and A.J. Schaeffer. 2007. Suppression of innate immune response in bladder by uropathogenic Escherichia coli. Infection&Immunity 75: 5353-5360 (PMCID: PMC2168307).
Rudick, C.N., Chen, M.C., Mongiu, A.K., and D.J. Klumpp. 2007. Organ crosstalk in pelvic pain relief. American Journal of Physiology–Regulatory, Integrative and Comparative Physiology 293: R1191-R1198.
Thumbikat, P., Waltenbaugh, C., Schaeffer, A.J., and D.J. Klumpp. 2006. Antigen-specific responses accelerate bacterial clearance in the bladder. Journal of Immunology 176: 3080-3086.
Klumpp, D.J., Rycyk, M.T, Chen, M.C., Thumbikat, P., Sengupta, S., and A.J. Schaeffer. 2006. Uropathogenic Eschericia coli induce extrinsic and intrinsic cascades to initiate urothelial apoptosis. Infection and Immunity 74: 5106-5113 (PMCID: PMC1594819).
Chen, M.C., Mudge, C.S., and D.J. Klumpp. 2006. Urothelial lesion formation is mediated by TNFR1 in neurogenic cystitis. American Journal of Physiology – Renal Physiology 291: F741-F749.
