Microbial regulation of host nutrient metabolism in gnotobiotic zebrafish

描述(由申请人提供)： 项目概述：目前肥胖和肥胖相关疾病的流行对公共卫生构成了重大挑战。因此，确定调节能量摄入、吸收和储存的新治疗策略是一个重要的目标。近年来，存在于消化道内的复杂微生物群落被证明是调节宿主能量储存的重要环境因素。我开发了一个新的斑马鱼诺生菌模型系统，并用它来表明微生物区系在调节宿主营养代谢中的作用在斑马鱼和哺乳动物之间已经进化保守。该项目的长期目标是了解微生物调节寄主营养代谢的分子机制。该项目的目的是利用斑马鱼体内观察寄主组织的能力以及遗传和化学筛选的能力，利用诺生菌斑马鱼模型确定影响寄主营养代谢的微生物因素。为了提供一个解释遗传和化学筛选结果的背景，我们对斑马鱼营养代谢的有限理解需要扩大。在特定目标1中，我将分析发育中的斑马鱼和成年斑马鱼的基因表达、脂肪含量和酶活性，以确定特定的代谢活动。负责调节宿主能量储存的微生物产物和基因尚不清楚，并代表着潜在的治疗靶点。在具体目标2中，这些微生物因子将通过化学和遗传筛选在灵生斑马鱼中识别，然后在灵生小鼠身上验证。该项目将为未来的研究奠定基础，并将导致对脊椎动物消化道内宿主-微生物相互作用的分子机制有更广泛的了解。 相关性：脂肪储存受到肠道中大量微生物群落的影响。这项研究的目标是了解肠道微生物是如何调节脂肪储存的。这一新知识可能导致治疗肥胖症和肥胖相关疾病的新疗法。

DESCRIPTION (provided by applicant): Project Summary: 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.