Functional and anatomical obstruction of the urinary bladder from congenital and acquired urologic abnormalities results in reduced bladder capacity, diminished compliance, urothelial dysfunction, and incontinence. Enterocystoplasty is utilized as the primary strategy to increase bladder capacity and decrease high intravesical pressures in order to preserve renal function in patients with obstructive bladder disease. However, the presence of absorptive intestinal epithelium in autologous gastrointestinal grafts frequently leads to serve complications such as chronic urinary tract infection, mucus production, and metabolic abnormalities once integrated into the urinary tract. Silk fibroin (SF) biomaterials provide an exceptional combination of physical characteristics including high tensile strength and elasticity, diverse processing flexibility, controllable degradability, and low immunogenicity to create ?off-the-shelf? scaffolds for treatment of obstructive bladder disease. Novel bladder reconstructive strategies employing bi-layer (BL) SF scaffolds in combination with anti- fibrotic therapeutics, halofuginone and ABT-263, will be investigated for their ability to restore normal urodynamic parameters and promote superior constructive remodeling in a newly developed, large animal model of partial bladder outlet obstruction (pBOO). Mechanistically, we will utilize state-of-the-art, integrated transcriptomic and proteomic expression profiling to understand how the severity of obstructive bladder damage controls key molecular regulators of bladder injury responses to produce diverse disease phenotypes. In this proposal, we will challenge the overall hypothesis that: acellular BLSF matrices in combination with anti-fibrotic compounds will provide a superior approach for restoring normal bladder function in chronically obstructed bladders in comparison to enterocystoplasty.
The specific aims of the application are:
Specific Aim 1 : Determine how the severity of pBOO influences molecular regulators of bladder injury responses.
Specific Aim 2 : Evaluate the impact of chronic pBOO on bladder regenerative processes following augmentation cystoplasty with acellular BLSF grafts.
Specific Aim 3 : Determine the efficacy of anti-fibrotic therapeutics in combination with BLSF scaffolds to ameliorate obstructed bladder dysfunction.
The results of this proposal are anticipated to produce a new tissue repair modality that will overcome current limitations in enterocystoplasty by creating a novel combinatorial strategy consisting of ?off-the-shelf? silk fibroin grafts coupled with anti-fibrotic therapeutics for reconstruction of chronically obstructed, diseased bladders. We also seek to uncover how the severity of obstructive bladder injury influences signaling networks to generate diverse disease subtypes with distinct levels of bladder dysfunction. We anticipate the results of this study will provide new information that is wider in scope than our specific goals and which may be applicable for repair of other urinary tract organs (ureter, urethra) in general.
