Chemical interrogation of metabolic tissue crosstalk

代谢组织串扰的化学研究

• 批准号: 10490441
• 负责人: Jonathan Z Long
• 金额: $ 79.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490441
• 关键词: Animals; Area; Atlases; Blood; Chemicals; Chemistry; Collection; Communication; Detection; Diabetes Mellitus; Diet; Endocrine; Event; Glucose; Goals; Homeostasis; In Vitro; Label; Lead; Lipids; Maps; Measures; Mediating; Metabolic; Metabolic Diseases; Methodology; Methods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Orphan; Pathway interactions; Peripheral; Physical activity; Physiologic pulse; Plasma; Proteins; Resolution; Signal Pathway; Technology; Temperature; Tissues; Vision; Work; cell type; combat; high reward; high risk; in vivo; insight; intercellular communication; interest; new therapeutic target; polypeptide

PROJECT SUMMARY. Peripheral metabolic tissues engage in pervasive inter-organ crosstalk to maintain systemic glucose and lipid homeostasis. This long-range intercellular communication is mediated by blood borne, secreted polypeptides. Over the last decade, there has been renewed interest in identifying additional proteins secreted from metabolic tissues. This is because the collection of secreted proteins (e.g., secretome) from metabolic cell types is large and also poorly characterized, and therefore many additional polypeptides that mediate peripheral tissue crosstalk likely remain to be discovered. It is not unreasonable to imagine that many of these orphan factors represent new signaling pathways and consequently potentially new therapeutic targets for obesity, diabetes, and related metabolic disorders. Typically, approaches to this problem have relied on surrogate methods that attempt to predict, rather than directly measure, in vivo polypeptide secretion events. In recent work, we have introduced an in vivo chemical methodology that enables a radically different strategy: to measure metabolic tissue secretomes directly in living animals (Wei et al., Nat. Chem. Biol. 2020). Importantly, this chemical strategy provides unique insights into the composition and dynamics of secretomes in mice that could not have been predicted by existing in vitro or computational approaches. This proposal seeks to further develop these chemical methodologies with the goal of generating a complete endocrine map of the secreted polypeptides that mediate peripheral metabolic tissue crosstalk. To achieve this goal, we will (1) produce a 6 organ, 15-cell type atlas of peripheral metabolic tissue polypeptide secretomes and determine how these secretomes are dynamically altered by metabolic perturbations such as obesity, diet, environmental temperature, and physical activity; (2) develop new in vivo chemistries that enable high-resolution mapping of secreted polypeptide fragments produced via proteolytic cleavage events; and (3) integrate metabolic tissue secretomes into endocrine circuits through in vivo chemical pulse-chase approaches. Successful completion of this high-risk, high-reward project will provide a chemical toolbox for dissecting cellular secretomes, open potentially important new areas in tissue crosstalk, and ultimately enable the long-term vision of “capturing” the pathways of tissue crosstalk to combat obesity, type 2 diabetes, and related metabolic disorders.

项目摘要。外周代谢组织参与普遍的器官间串扰以维持 这种长程细胞间通讯是由血液介导的。 在过去的十年中，人们对鉴定额外的多肽产生了新的兴趣。 从代谢组织分泌的蛋白质，这是因为分泌蛋白质的集合（例如分泌蛋白组）。 来自代谢细胞类型的多肽很大，而且特征也很差，因此有许多额外的多肽 介导外周组织串扰的机制可能还有待发现。这样的想象并非没有道理。 许多这些孤儿因子代表了新的信号通路，因此可能是新的治疗方法 通常，解决这一问题的方法依赖于肥胖、糖尿病和相关代谢紊乱的目标。 尝试预测而不是直接测量体内多肽分泌的替代方法 在最近的工作中，我们引入了一种体内化学方法，可以实现完全不同的结果。 策略：直接测量活体动物的代谢组织分泌蛋白组（Wei et al., Nat. Chem. Biol. 2020）。 重要的是，这种化学策略为分泌蛋白组的组成和动力学提供了独特的见解 在小鼠中，现有的体外或计算方法无法预测这一点。 寻求进一步开发这些化学方法，以生成完整的内分泌图 为了实现这一目标，我们将研究介导外周代谢组织串扰的分泌多肽。 (1) 制作外周代谢组织多肽分泌组的6个器官、15个细胞类型图谱并测定 这些分泌蛋白组如何因肥胖、饮食、环境等代谢扰动而动态改变 温度和身体活动；（2）开发新的体内化学物质，以实现高分辨率绘图 通过蛋白水解裂解事件产生的分泌的多肽片段；以及（3）整合代谢组织； 通过体内化学脉冲追踪方法成功完成分泌蛋白组进入内分泌回路。 这个高风险、高回报的项目将提供一个用于解剖细胞分泌体的化学工具箱，开放 组织串扰中潜在的重要新领域，并最终实现“捕获”的长期愿景 对抗肥胖、2 型糖尿病和相关代谢紊乱的组织串扰途径。