Research Projects | Overview
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic condition primarily affecting women. 3.2 to 7.9 million women over the age of 18 in the US suffer from IC/PBS. With no current effective treatments IC/PBS causes unrelenting bladder pain, frequent urination, and discomfort. Extreme cases show a huge impact on quality of life with patients having to urinate over 60 times a day and seven times throughout the night. Moreover, in several recent clinical trials, various compounds failed to show any promising effectiveness against IC/PBS. The direct and indirect costs for US IC/PBS patients and their families, including increased medical expenses and decreased work productivity, is estimated to be on the order of $21.1 billion dollars annually.
Key Factors in the Disease
Although the etiology of IC/PBS is poorly understood, a large body of literature implicates urothelial cell injury and mast cell activation as key factors in the pathogenesis of the disease. Pathologic studies have shown patient symptoms are correlated with lesions of the urothelium lining the bladder and the accumulation of mast cells throughout all layers. Contributing mechanisms include deficiencies in the glycosaminoglycan (GAG) layer of the bladder and mast cell-mediated neuro-inflammation.
The Oottamasathien laboratory has developed a mouse model of inflammatory cystitis that is physiologically relevant, biologically based, non-infectious, non-chemically induced, and recapitulates key clinical aspects of IC/PBS using the natural catheliciden (LL-37). Through this model we have shown that LL-37 induces cystitis, both acutely and chronically, with severity of inflammation being dose dependent. After a single insult of LL-37, bladders demonstrated severe inflammation with global erythema, hemorrhage, edema and hypervascularity.
Our most recent work has implicated mast cells as a key cell type in driving both inflammation and pain in our LL-37 induced bladder injury model. Our model has also yielded prolonged pain responses to be independent of acute inflammation, more closely mimicking what has been observed in patients with IC/PBS. In addition, our patented SAGE compounds have been demonstrated to substantially attenuate both inflammation and pain, and may represent a new class of non-opioid based analgesics for future therapeutic use. Finally, recent work with innovative thermosensitive biopolymers have demonstrated a more sustained delivery system of therapeutics to target organs of interest.
Further mechanistic studies are being performed to hopefully one day fully understand and elucidate the entire mechanistic role LL-37 plays in IC/PBS, both acutely and chronically. Our lab is making great headway in understanding and treating IC/PBS, bridging the gap between bench top to bedside.
In addition to our bladder inflammation and pain body of work, in 2018 in conjunction with my lab and collaborative team at the University of Utah, we were awarded a 5 year NIH R01 grant (R01CA227225-01A1) to further investigate innovative therapeutic approaches to treat radiation induced proctitis. The goal of this work is to better elucidate the role of mast cells in disease propagation in patients receiving lower abdominal pelvic radiotherapy. In addition, a large focus is to better understand the thermoresponsive properties of our silk-elastin like protein polymer system and to optimize SAGE drug delivery within the rectum. Overall, our research efforts continue to represent significant, innovative, and high-impact science that continues to move the field of urology forward.