The current epidemic of obesity and obesity-related disorders are presenting major public health challenges. The identification of new therapeutic strategies for regulating energy intake, absorption, and storage is therefore an important goal. The complex microbial community residing within the digestive tract has recently been shown to be an important environmental factor regulating host energy storage. I have developed a new gnotobiotic zebrafish model system, and used it to show that the roles of the microbiota in modulation of host nutrient metabolism have been evolutionary conserved between zebrafish and mammals. The long-term objective of this project is to understand the molecular mechanisms underlying microbial regulation of host nutrient metabolism. This project aims to identify the microbial factors that influence host nutrient metabolism using the gnotobiotic zebrafish model, taking advantage of its capacity for in vivo observation of host tissues, and for genetic and chemical screens. To provide a context for interpreting results from genetic and chemical screens, our limited understanding of nutrient metabolism in zebrafish needs to be expanded.
In Specific Aim 1, I will assay gene expression, lipid content, and enzymatic activities to locate specific metabolic activities in developing and adult zebrafish. The microbial products and genes responsible for modulation of host energy storage are unknown, and represent potential therapeutic targets.
In Specific Aim 2, these microbial factors will be identified through chemical and genetic screens in gnotobiotic zebrafish, and then validated in gnotobiotic mice. This project will establish a foundation for future studies and will lead to a more extensive understanding of the molecular mechanisms underlying host-microbial interactions in the vertebrate digestive tract. Relevance: Fat storage is influenced by the large community of microorganisms residing in the intestine. This goal of this research is to understand how intestinal microorganisms regulate fat storage. This new knowledge could lead to novel therapies for treatment of obesity and obesity-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK073695-04
Application #
7618016
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$127,144
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Minchin, J E N; Rawls, J F (2017) In vivo imaging and quantification of regional adiposity in zebrafish. Methods Cell Biol 138:3-27
Kanther, Michelle; Tomkovich, Sarah; Xiaolun, Sun et al. (2014) Commensal microbiota stimulate systemic neutrophil migration through induction of serum amyloid A. Cell Microbiol 16:1053-67
Camp, J Gray; Jazwa, Amelia L; Trent, Chad M et al. (2012) Intronic cis-regulatory modules mediate tissue-specific and microbial control of angptl4/fiaf transcription. PLoS Genet 8:e1002585
Sanapareddy, Nina; Legge, Ryan M; Jovov, Biljana et al. (2012) Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans. ISME J 6:1858-68
Minchin, James E N; Rawls, John F (2011) In vivo analysis of white adipose tissue in zebrafish. Methods Cell Biol 105:63-86
Roeselers, Guus; Mittge, Erika K; Stephens, W Zac et al. (2011) Evidence for a core gut microbiota in the zebrafish. ISME J 5:1595-608
Kanther, Michelle; Sun, Xiaolun; Mühlbauer, Marcus et al. (2011) Microbial colonization induces dynamic temporal and spatial patterns of NF-?B activation in the zebrafish digestive tract. Gastroenterology 141:197-207
Volkman, Hannah E; Pozos, Tamara C; Zheng, John et al. (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327:466-9
Kanther, Michelle; Rawls, John F (2010) Host-microbe interactions in the developing zebrafish. Curr Opin Immunol 22:10-9
Shen, Xiang Jun; Rawls, John F; Randall, Thomas et al. (2010) Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes 1:138-47

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