Quantifying Enteric Metabolism of Branched-chain Amino Acids in Relation to Other Dietary and Microbiota Nutrients

项目摘要/摘要 研究：改善肠道胰岛素分泌和糖异生的药物前景看好 治疗肥胖症和糖尿病，但其作用机制知之甚少，限制了它们的 申请。必需支链氨基酸(BCAA)的高位循环池及其 代谢物一直与肥胖和糖尿病有关，研究主要集中在肝脏和 不考虑肠道氨基酸代谢的肌肉蛋白质代谢。循环中的支链氨基酸 在哺乳动物中，必须要么来自饮食，要么来自驻留在管腔中的微生物区系，这些微生物区系向上调节其 BCAA酶在肥胖和胰岛素抵抗动物模型中的表达。氨基酸谷氨酰胺提供 在禁食和进食状态下显著增加肠道能量，减少肠道细胞对葡萄糖的氧化，但它 不知道支链氨基酸是否会导致类似的新陈代谢变化。肠道也代谢微生物产生的营养物质。 像丙酸一样，在禁食和喂养状态下产生能量和代谢物。在隔离状态下，微生物产生 众所周知，营养素和支链氨基酸可以刺激营养感官中肽-胰岛素激素的分泌。 细胞排列在管腔内，协调全身新陈代谢，为营养负荷做准备。递增反应 肥胖和糖尿病患者的肠道葡萄糖代谢降低，但驱动机制 人们对监管失调知之甚少。微生物产生的营养物质和饮食营养物质之间的协同作用可能起到一定作用 内分泌失调和/或改变肠道代谢，影响循环代谢物池。直接测量 饮食和循环中支链氨基酸的代谢将量化肠道代谢对 循环中的支链氨基酸和代谢物池。确定肠道支链氨基酸代谢是否与代谢相互作用 微生物区系产生的营养物质和蔗糖的比例将显示肠道代谢是否对支链氨基酸的升高起到作用 以及与代谢性疾病相关的代谢物库。 应聘者/培训：从长远来看，我计划从事一项独立的研究生涯，管理一个跨学科 实验室开发益生菌和/或药物，改变肠道营养处理以治疗代谢 疾病。为了追求这个目标，我组织了研究目标和一个指导团队，为我提供 基础知识和培训对我的进步至关重要。怀特博士是一位新陈代谢生理学家， 许多备受瞩目的关于支链氨基酸在其他组织中代谢的出版物，将平衡更多由微生物驱动的 由约翰·罗尔斯博士提供的指导。我们已经详细说明了我将通过他们的培训或 正式课程和详细的社区会议，我将参加，以建立过渡到必要的技能 独立。一个更大的委员会，包括杜克大学新陈代谢生理研究所和 微生物群中心和医学部消化科科长将 监督我的技术和专业进展，以确保提供足够的支持。

Project Summary/Abstract Research: Pharmaceuticals modifying intestinal incretin secretion and gluconeogenesis are promising new therapies for obesity and diabetes mellitus, but their mechanisms of action are poorly understood limiting their application. Elevated circulating pools of the essential branched-chain amino acids (BCAAs) and their metabolites are consistently associated with obesity and diabetes with research primarily focused on liver and muscle metabolism of dietary protein without considering intestine amino acid metabolism. Circulating BCAAs in mammals must either originate from the diet or the microbiota residing in the lumen that upregulates its expression of BCAA enzymes in obese and insulin-resistant animal models. The amino acid glutamine provides significant energy to the intestine in fasted and fed states, reducing glucose oxidation by intestine cells but it is not known if BCAAs drive similar metabolic changes. The intestine also metabolizes microbe-produced nutrients like propionate in fasted and fed states for energy and metabolite production. In isolation, microbe-produced nutrients and BCAAs are known to stimulate the secretion of peptide incretin hormones from nutrient sensing cells lining the lumen that coordinate whole body metabolism in preparation for a nutrient load. Incretin response and enteric glucose metabolism are reduced in obese and diabetic patients but the mechanisms driving dysregulation are poorly understood. Synergy between microbe-produced and dietary nutrients could contribute to incretin dysregulation and/or alter enteric metabolic effecting circulating metabolite pools. Directly measuring the metabolism of dietary and circulating BCAAs will quantify the contribution of intestine metabolism to circulating BCAA and metabolite pools. Determining if intestine BCAA metabolism interacts with the metabolism of microbiota-produced nutrients and sucrose will show if intestine metabolism contributes to the elevated BCAA and metabolite pools associated with metabolic disease. Candidate/Training: Long term, I plan to pursue an independent research career managing an interdisciplinary laboratory developing probiotics and/or pharmaceuticals that change intestine nutrient handling to treat metabolic disease. In pursuit of this goal, I have assembled research aims and a mentoring team to provide me with the foundational knowledge and training essential to my progress. Dr. White, an expert metabolic physiologist with many high-profile publications on BCAA metabolism in other tissues, will balance the more microbiology-driven mentorship provided by Dr. John Rawls. We have detailed the technical skills I will gain through their training or formal courses and detailed the community meetings I will attend to build the necessary skills to transition to independence. A larger committee including the directors of Duke’s Metabolic Physiology Institute and Microbiome Center as well as the Chief of the Division of Gastroenterology in the Department of Medicine will monitor my technical and professional progress to ensure adequate support is provided.