Crosstalk between Thrombospondin-1 and proliferation of bladder epithelial cells in urinary tract infection during chronic lymphocytic leukemia

• Applicant: Professor Dr. Daniel Robert Engel
• Subject Area: Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539301313

Proliferation of bladder epithelial cells (BEC) during urinary tract infection (UTI) is an important mecha-nism for maintaining the physical barrier after urothelial loss caused by hemolytic uropathogenic E.coli (UPEC) and urothelial shedding. Patients with chronic lymphocytic leukemia (CLL), the most common form of leukemia are susceptible to UTI induced by UPEC. Preliminary data indicated that infiltration of CLL cells into the urinary bladder coincided with abolished proliferation of BEC in UTI and increased infection strength. Using state-of-the-art mass spectrometry and microscopy, we found that the pro-duction of Thrombospondin-1 (TSP1), which is an essential molecule for the secretion of Tumor Growth Factor b (TGF-b) from the latency-associated peptide (LAP), was severely reduced in CLL. Pre-viously, the TGF-b-axis was shown to induce urothelial proliferation, suggesting that reduced TSP1-dependent secretion of mature TGF-b in CLL might diminish urothelial proliferation in UTI, leading to increased infection strength. To study the mechanisms of altered TSP1 expression and urothelial proliferation in CLL and UTI, the following aims will be pursued in this study: 1. Characterize the cellular and molecular changes of the tissue microenvironment in UTI and CLL. 2. Study the proteomic changes of BEC in UTI and CLL. 3. Analyze the mechanism of BEC proliferation in an in vitro model. 4. Evaluate the impact of TSP1 on the proliferation of BEC in vivo and therapeutically restore TSP1 levels and BEC proliferation in CLL to reduce bacterial burden.

• DFG Programme: Research Grants