Mechanisms of Cellular Adaptation in Cystitis

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 DESCRIPTION (provided by applicant): The following proposal outlines my plan to become an independent researcher focused on finding solutions for patients with bladder inflammation. I am an Assistant Professor in the Department of Urologic Surgery at Vanderbilt University with fellowship training in Pediatric Urology. I will devote the next 5 years of my career to the primar goal of developing the scientific and professional capacity to be an independent scientist. Cystitis, or bladder inflammation, is a prevalent problem that affects millions of Americans every year as a result of urinary tract infections, bladder obstruction, radiation, and chemotherapy. Patients who develop bladder damage from cystitis suffer from incontinence, bladder pain, hematuria and even renal damage. Many patients with bladder inflammation will ultimately require invasive bladder surgery. A fundamental knowledge gap exists in understanding how the urothelial cells that line the bladder adapt following injury and respond during the ensuing inflammation. Gaining increased insight into this problem is important for developing treatments to mitigate the short and long term damage caused by cystitis. My development into an independent researcher will enable me to ask the important scientific questions and then seek out the answers to improve the lives of patients with bladder inflammation. I will work to establish my independent capacity through a structured program of mentored scientific experiments and career development activities. These activities will consist of regular scientific interaction, graduate school coursework, technical training, intellectual interactions, on-campus seminars, grant writing courses and laboratory meetings. Mentorship will be the centerpiece of this project and an advisory committee of experienced scientists will guide my scientific and career development. My institution has a multitude of resources to foster career development and I will make full use of those opportunities. Emerging evidence indicates that acute activation of the Hypoxia inducible factor (HIF) pathway is beneficial for epithelial cells in the setting of injury and inflammation. We have generated preliminary data indicating that HIF activation occurs in the bladder following injury. The key to unlocking the potential benefits of the HIF signaling pathway lies in Prolyl-4-hydroxylase domain-containing (PHD) proteins. PHDs are the up-stream oxygen sensitive enzymes that antagonize HIF activity. New evidence from multiple different models of organ injury shows that inhibiting PHD activity leads to activation of the HIF pathway and subsequently promotes epithelial survival and protection. We have shown that PHD inhibition is protective in the setting of urothelial injury and cystitis. Based on our preliminary data and published data in other organs, we hypothesize that urothelial adaptation after injury is dependent upon HIF-mediated gene transcription and that PHD inhibition is the critical first step in this process. We will test the central hypothesis by executing three specifi aims. Aim 1 seeks to understand how inhibition of individual PHD2 family member protects the bladder from injury using mouse models of cystitis. Aim 2 will explore the HIF-mediated transcriptional response of cultured urothelial cells under conditions of PHD inhibition. Finally, Aim 3 will evaluate the integral role of urothelial-cell specific HIF expression during injury-induced cystitis.