Cancer survivors are at risk for developing radiation cystitis (RC) after radiation therapy. RC is a debilitating bladder and may be life-threatening. Current therapies are inadequate and can have severe life changing side-effects. The absence of reliable treatment and early diagnostic markers is in part due to limited comprehension of the histological and molecular changes associated with the progression of this condition. I hypothesize that radiation-induced damage to the bladder vasculature drives the chronic inflammation, fibrosis and hematuria associated with RC. This hypothesis will be addressed through three specific aims: 1. Determine the effect of radiation therapy on bladder vasculature function, 2. Assess and target the inflammation in an animal model of RC, and 3. Validate urinary candidate biomarkers for early detection of RC. The study design includes assessing functional changes of endothelial cells and determining changes in ICAM-1 expression and its role in immune cell recruitment in response to irradiation. Non-irradiated and cyclophosphamide treated cells will serve as negative and positive controls respectively. Using a mouse model of RC, a timeline of molecular and histological bladder changes in response to radiation will be determined. Non-irradiated bladders and cyclophosphamide-induced cystitis in mice will be used as negative and positive controls for these studies respectively. Finally urine samples from RC patients with a history of prostate or cervical cancer will be used to develop a biomarker for RC. Controls consist of age-matched male and female urine samples. As a cancer survivor and a scientist, my ultimate career goal is to improve the quality of life of cancer survivors through my research. I plan on achieving this goal by becoming an independent translation investigator, focusing my research on urological complications from cancer therapies, and implementing my research findings into the clinic. Through my past research track record, I have extensive experience in basic science techniques in vascular and cancer biology. The additional necessary skills to successfully complete this research and training proposal will be acquired through mentorship and coursework in translational research, radiation, and biostatistics. In addition, I will be receiving practical training in viral infections and pathology. I will be receiving continuous mentorship from Drs. Chancellor and Lamb. Drs. Kanai and Wilson will serve as co-mentors. My mentors have a history of successful mentorship of NIH scientists and we have a superb and supportive training environment here at Beaumont Research Institute and Oakland University William Beaumont School of Medicine. The outcome of our studies can significantly improve the quality of life of many cancer survivors that are suffering with severe bladder complications due to radiation therapy. These studies could lead to finding effective therapy for RC as well as a urine biomarker for early detection of RC. This research study has great potential to improve the quality of life of cancer survivors suffering from this debilitating condition.
Radiation cystitis is a debilitating side-effect from pelvic cancer radiation treatment with severe unmet medical needs. This research will develop an understanding of how irradiation induces damage to the vasculature and of how bladder hemorrhaging develops. In addition, these studies will directly impact patient care as we aim to test tacrolimus as a new therapy for radiation cystitis in an established animal model and identify urine biomarkers for early detection of radiation cystitis.
| Wegner, Kyle A; Abler, Lisa L; Oakes, Steven R et al. (2018) Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots. Am J Physiol Renal Physiol 315:F1067-F1080 |
