Intestinal dysfunction may impair BA uptake and feedback inhibition of hepatic bile acid (BA) synthesis, thereby resulting in BA malabsorption (BAM). Increased fecal BAs promote colon pathology;cholerrheic diarrhea and possibly neoplasia. Intestinal BA uptake is mediated primarily by the ileal Apical Sodium-dependent Bile Acid Transporter (ASBT;SLC10A2). Reduced ASBT function decreases BA absorption;Asbt-null mice have increased fecal BAs. In primary BAM impaired feedback inhibition by intestinal fibroblast growth factor-19 (FGF19) increases BA synthesis and intestinal BA levels overwhelm BA transporter capacity. Fgf15-null mice mimic primary BAM;they also have increased fecal BAs. Our recently published in vitro and in silico data indicate that commonly-used drugs, including statins, inhibit ASBT function. If drugs impair ASBT function in vivo, altered BA transport may result in unanticipated side-effects, including colon pathology. Current tools to measure BA transport and distribution in vivo are limited. To remedy this limitation, we conceived an innovative approach in live animals that utilizes combined proton (1H)-fluorine (19F) magnetic resonance imaging (MRI);a novel methodology with translational potential for clinical practice. R21 funding will support a research team uniquely qualified to create and test (in vitro and in vivo) multi-fluorinated, non-radioactive (19F) BAs (MFBA) using biochemical methods and live animal MRI: Dr. Raufman, an expert in BA effects on colon epithelium;Dr. Polli, an expert in measuring BA transport in vitro;Dr. Dawson, an expert in measuring BA transport in vivo;Dr. Yu, an expert chemist who developed 19F-imaging tracer (19FIT);and Dr. Xu, an expert in small animal MRI. We will design, create and test two classes of 19F-labeled agents: (1) MFBA that are bound and transported by ASBT [e.g. 19F-labeled chenodeoxycholic acid (19F3-CDCA) with three 19F atoms/molecule] and (2) Inactive control agents neither bound nor transported by ASBT (e.g. 19FIT). To accomplish these goals, we propose two Specific Aims: >1. Create multi-fluorinated BAs and test in vitro stability and interaction with enteric BA transporters. >2. Test in vivo stability and transport of multi-fluorinated BAs in WT, Slc10a2- /- and Fgf15-/- mice using biochemical methods and live-animal magnetic resonance imaging. Our multidisciplinary team includes established investigators with unquestioned expertise in measuring bile acid transport. This team is uniquely qualified to develop this innovative technology based on magnetic resonance imaging of newly-created non-radioactive, fluorine-labeled bile acids that can be used to obtain both temporal and spatial information on bile acid transport in live animals and humans.
In addition to their traditional role as detergents that facilitate fat absorption, bile acids are potent signaling molecules that affect multiple organs;they modulate gut motility and hormone production, colon physiology and cancer susceptibility, and alter vascular tone, glucose metabolism, lipid metabolism and energy utilization. To understand these complex actions of bile acids new technology is required that permits simultaneous monitoring of bile acid levels in the gastrointestinal tract and metabolic tissues. In this R21 application, we propose to develop an innovative technology based on magnetic resonance imaging of newly-created non- radioactive fluorine-labeled bile acids that can be used to obtain both temporal and spatial information in live animals and humans.
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|Dong, Zhongqi; Ekins, Sean; Polli, James E (2015) A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide. Int J Pharm 478:88-95|
|Raufman, Jean-Pierre; Dawson, Paul A; Rao, Anuradha et al. (2015) Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis 36:1193-200|
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|Dong, Zhongqi; Ekins, Sean; Polli, James E (2015) Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition. Eur J Pharm Sci 66:1-9|
|Vivian, Diana; Polli, James E (2014) Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver. Int J Pharm 475:597-604|
|Vivian, Diana; Cheng, Kunrong; Khurana, Sandeep et al. (2014) Design and evaluation of a novel trifluorinated imaging agent for assessment of bile acid transport using fluorine magnetic resonance imaging. J Pharm Sci 103:3782-92|
|Cheng, Kunrong; Xie, Guofeng; Khurana, Sandeep et al. (2014) Divergent effects of muscarinic receptor subtype gene ablation on murine colon tumorigenesis reveals association of M3R and zinc finger protein 277 expression in colon neoplasia. Mol Cancer 13:77|
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