Microbial regulation of host nutrient metabolism in gnotobiotic zebrafish

描述（由申请人提供）： 项目概述：目前肥胖症和肥胖相关疾病的流行正在提出重大的公共卫生挑战。因此，确定用于调节能量摄入、吸收和储存的新的治疗策略是一个重要的目标。消化道内复杂的微生物群落最近被证明是调节宿主能量储存的重要环境因素。我已经开发了一个新的gnotobiotic斑马鱼模型系统，并使用它来表明，在调节宿主营养代谢的微生物群的作用已经在斑马鱼和哺乳动物之间进化保守。本项目的长期目标是了解微生物调节宿主营养代谢的分子机制。该项目旨在利用斑马鱼模型，利用其对宿主组织的体内观察以及遗传和化学筛选的能力，确定影响宿主营养代谢的微生物因素。为了解释遗传和化学筛选的结果，我们对斑马鱼营养代谢的有限理解需要扩大。在具体目标1中，我将分析基因表达，脂质含量和酶活性，以定位发育和成年斑马鱼的特定代谢活动。负责调节宿主能量储存的微生物产物和基因是未知的，并且代表潜在的治疗靶点。在具体目标2中，这些微生物因子将通过在gnotobiotic斑马鱼中进行化学和遗传筛选来鉴定，然后在gnotobiotic小鼠中进行验证。该项目将为未来的研究奠定基础，并将导致更广泛的了解脊椎动物消化道中宿主-微生物相互作用的分子机制。 相关性：脂肪储存受到肠道内大量微生物的影响。这项研究的目的是了解肠道微生物如何调节脂肪储存。这一新知识可能会导致治疗肥胖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.