Forster & Bates

i4Kids Pilot Grant FY22
Project Period: July 1, 2021 - December 31, 2022
Award Amount: $50,000

Urinary tract infections (UTI) are a significant source of morbidity in children with spina bifida that have neuropathic bladders. Further, healthcare costs for UTI in children with spina bifida are 13 times higher than in the general pediatrics population. One likely reason for increased UTI susceptibility in children with spina bifida is ongoing urothelial injury and/or poor urothelial repair. Direct examination of urothelium from children revealed evidence of hyperplasia/proliferation and inflammation consistent with ongoing injury, and attenuated uroplakin expression, suggesting poor repair. Similarly, a mouse model of spinal cord injury (SCI) with neuropathic bladder revealed ongoing urothelial proliferation, implying persistent injury, and showed evidence of poor urothelial repair including reduced uroplakin staining and ectopic expression of basal cell markers at the outer urothelial surface. Ongoing disruption of the urothelium would likely allow bacteria to easily penetrate the bladder to cause infection and compromise the innate immune mechanisms normally provided by the urothelium.

Urothelium can also be injured by cyclophosphamide, which also increases risks of UTI in preclinical models and in humans. The Bates lab showed that cyclophosphamide induces urothelial apoptosis and faulty repair similar to mice with SCI/neuropathic bladder (reduced uroplakin and ectopic basal cell marker staining). The Bates lab also found that pre-treatment with systemic keratinocyte growth factor (KGF) blocked urothelial apoptosis and led to higher fidelity urothelial repair, with proper differentiation and suppression of ectopic basal cell markers. The Bates lab also found that KGF activated AKT, which can block apoptosis. Additionally, the group found that chemical inhibition of AKT impedes the anti-apoptotic effects of KGF with cyclophosphamide (unpublished). Thus, KGF/AKT signaling appears to block urothelial apoptosis and drive high fidelity repair after cyclophosphamide. However, effects of KGF on urothelial injury or repair in neuropathic bladders are unknown.

Together, our central hypothesis is that KGF/AKT suppresses urothelial injury and faulty repair in neuropathic bladders, leading to decreased susceptibility to UTI. To test the hypothesis, we will leverage expertise of the Forster lab in mouse UTI models and the Bates lab in mouse urothelial (and kidney) injury for the following aim:

Aim:

1. Assess how KGF/AKT affects urothelial injury/repair and UTI susceptibility.