This is an application for a K08 award for Dr. Bittoo Kanwar, a fellow in pediatric gastroenterology, hepatology, and nutrition at the University of California, San Francisco, who is establishing himself as a young investigator in non-invasive means to study the immune response in inflammatory bowel disease (IBD). This K08 award will provide Dr. Kanwar with the support necessary to accomplish the following goals: (1) to gain expertise in the utility of antibody-based PET (immuno-PET) in IBD;(2) using these novel non-invasive modalities, correlate those findings with biologic processes occurring in vivo at the mucosal surface;(3) to optimize these methods and test their efficacy and sensitivity on human cells prior to ultimate translation to human subjects;and (4) to develop an independent research career as a translational investigator. To achieve these goals, Dr. Kanwar has assembled a mentoring team comprised of a primary mentor, Dr. Joseph """"""""Mike"""""""" McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts basic and translational research in infectious disease and inflammatory disorders (in particular HIV infection), and three co-mentors: Dr. Melvin B. Heyman, a pediatric gastroenterologist with expertise in the translational and clinical investigation of IBD;Dr. Averil Ma, director of The Colitis and Crohn's Disease Center at UCSF;and Dr. Simon Williams, a Senior Scientist at Genentech, Inc., and an expert in PET imaging and analysis of various inflammatory conditions, including IBD. Technologies to quantitate the mucosal immune response in vivo in a non-invasive manner is [sic] essential to understanding disease pathogenesis and response to therapy in both small animal models and human patients alike. These studies are proposed to answer the question: is it possible to quantitate and visualize specific subpopulations of immune cells implicit in disease pathogenesis in IBD? Dr. Kanwar will leverage the resources available at both UCSF and Genentech to: determine the extent to which specific subpopulations of murine immune cells can be detected in vivo using radiolabeled monoclonal antibodies and Fab fragments (Aim 1), determine the sensitivity of immuno-PET in the context of murine IBD (Aim 2), and to extend these technologies to the visualization and quantitation of human cells in the heterochimeric SCID-hu Thy/Liv/LN mouse - a mouse model with circulating and functional human immune cells (Aim 3). This will provide Dr. Kanwar the necessary skills and preliminary data in which these imaging agents and technologies, optimized during the course of the 5-year K08 award period, can be translated to human subjects as an R01 grant application.

Public Health Relevance

Improving the understanding of cell-specific immune responses in IBD in a non-invasive in vivo manner will be critical to the development and testing of future therapies, both in basic science research and clinical practice. The optimization of these technologies will impact the medical burden that IBD has placed on the public as whole as novel imaging modalities will expand our knowledge about IBD and lead to appropriate - and cell specific - treatment strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Lowe, Margaret M; Mold, Jeff E; Kanwar, Bittoo et al. (2014) Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS One 9:e87877
Pak, Seung; Holland, Nina; Garnett, Elizabeth A et al. (2012) Cytokine profiles in peripheral blood of children and adults with Crohn disease. J Pediatr Gastroenterol Nutr 54:769-75
Hartigan-O'Connor, Dennis J; Abel, Kristina; Van Rompay, Koen K A et al. (2012) SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment. Sci Transl Med 4:136ra69
Favre, David; Mold, Jeff; Hunt, Peter W et al. (2010) Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2:32ra36
Kanwar, Bittoo; Favre, David; McCune, Joseph M (2010) Th17 and regulatory T cells: implications for AIDS pathogenesis. Curr Opin HIV AIDS 5:151-7