Therapeutic Monitoring and Targeting of Neutrophil Activation in Pediatric IBD

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 DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) currently affect 1.4 million people in the United States including approximately 50,000 children. Despite vast improvements in medical therapy, a large majority of inflammatory bowel disease (IBD) patients will require abdominal surgery secondary to progressive intestinal inflammation. Additionally, IBD related morbidity negatively impacts patient's quality of life and is associated with steep increases in health care costs. The primary goal of my proposed career development award is to acquire additional comprehensive training in biostatistics and advanced immunology, acquire the skills necessary to build multicenter collaborations, and further examine our biomarker in a longitudinal cohort with the goal to lead investigator-initiated clinica trials designed to improve the long-term efficacy of IBD therapy. I am an Assistant Professor of Pediatrics and a board-certified pediatric gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Cincinnati Children's Hospital Medical Center (CCHMC). The global mission of CCHMC is to improve child health and transform care delivery through fully integrated research, education and innovation. CCHMC is dedicated to the development of young investigators with several institutional funding opportunities, numerous core resources and fosters a collaborative research environment. The Digestive Health Center (DHC) is one of only 17 NIDDK-funded Digestive Disease Research Core Centers in the United States and provides access to various cores services at a discounted price. In addition, the Office for Clinical and Translational Research (OCTR) and the Clinical Translation Research Center (CTRC) offers consultative support in developing clinical trials, study monitoring, training and statistical analysis. In addition, CCHMC is internationally recognized for its superior clinical care of pediatric patients and cares for >600 children with IBD. Lee A. Denson, MD is a nationally recognized leader in translational and clinical IBD research and will serve as my primary mentor. Yi Zheng, PhD is internationally recognized for his work on the cell signaling role of Rho family small GTPases and the development of therapeutic agents that target the Rho GTPase signaling axis and will provide co-mentorship during this award. My near-term goal is obtain additional expertise in statistical analysis by earning a Master of Science in Clinical and Translational Research, innate immunity, neutrophil function analysis, clinical trial design and conduct the longitudinal assessment of our novel neutrophil biomarker for monitoring and predicting treatment response in children with IBD. We will also explore the pathogenic role of activated neutrophils in gut injury to further develop and test novel pharmaceutical agents for IBD patients with poor responses to current therapy. My long-term goals are to apply the knowledge and skills learned during this award to obtain independent funding as a physician-scientist conducting innovative clinical and translational research. Specifically, following the additional training, I will form a multicenter collaboration o conduct a comparative effectiveness clinical trial to improve short and long term response rates to anti-TNF therapy in pediatric IBD. The treat-to-target strategy has emerged as a novel approach to frequently assess treatment response as optimized medical treatment that meets specific targets is the key to prevent gut injury and reverse the current lifetime risks of surgery associated with severe IBD. Although the treat-to-target strategy is in its infancy, it is recognizd that frequent monitoring with disease specific biomarkers may alter outcomes by alerting clinicians prior to clinically overt symptoms as intestinal inflammatory activity may persist even in the absence of gastrointestinal symptoms. The development of novel biomarkers is vital to the success of this treatment strategy as an accurate biomarker would allow clinicians to objectively assess ongoing intestinal inflammation and develop strategies to achieve mucosal healing (absence of intestinal ulcers by endoscopy) as it is the only established predictive factor for sustained remission. Existing IBD biomarkers reflect the non-specific inflammatory burden and are not directly implicated in the pathogenesis of gut injury while the disease-specific clinical indices grossly underestimate intestinal inflammation. Thus, there is a critical need for biomarker that accurately detects endoscopic inflammation/healing and is implicated in IBD pathogenesis as it would provide an IBD specific target to direct therapy. In Aim 1, we will extend our previous work and further define the polymorphonuclear leukocyte (PMN) CD64 index (a marker for CD64 surface expression) as an accurate biomarker of endoscopic severity and treatment response. To test this, we will enroll IBD patients who have been referred for colonoscopy and determine the capacity of the PMN CD64 index to discriminate between endoscopic severity scores (mucosal healing, mild, moderate and severe) in both Crohn's disease and ulcerative colitis. We will also determine the ability of the PMN CD64 index to predict the likelihood of early treatment response and sustained remission in a longitudinal cohort of IBD patients initiating infliximab therapy. In Aim 2, we will further explore the effect f elevated PMN CD64 expression on intestinal epithelial injury in IBD by evaluating the production of reactive oxygen species from peripheral blood and intestinal lamina propria derived PMN's. Additionally we will test the effect a novel therapeutic compound has on PMN functions in vitro as the small molecule targets activated PMN's and would function as an alternative therapy for IBD patients with a poor response to current therapies.