Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3

通过轴突引导分子 Slit3 调节脂肪组织重塑

• 批准号: 10645972
• 负责人: Farnaz Shamsi
• 金额: $ 12.06万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-27 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645972
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Binding; Biological; Blood Vessels; Body Temperature; Brown Fat; C-terminal; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cells; Cellular Phone; Chemicals; Child; Chronic; Co-Immunoprecipitations; Communities; Data; Development; Diabetes Mellitus; Endothelial Cells; Energy Metabolism; Environment; Family; Fatty acid glycerol esters; Gene Delivery; Health; Health Priorities; Healthcare; Human; Immunohistochemistry; In Vitro; Indirect Calorimetry; Length; Ligands; Lipolysis; Mediating; Metabolic Diseases; Methods; Modeling; Molecular; Mus; N-terminal; Nerve; Neurites; Norepinephrine; Obesity; Oxygen; Pathway interactions; Play; Process; Regulation; Research; Risk; Role; Semaphorins; Signal Transduction; Stimulus; Testing; Thermogenesis; Tissue imaging; Tissues; United States National Institutes of Health; Vascular Endothelial Cell; adipokines; angiogenesis; axon guidance; blood perfusion; cancer type; cardiometabolism; combat; in vivo; in vivo Model; insight; lipid biosynthesis; member; nerve supply; obesity treatment; overexpression; prevent; progenitor; receptor; single-cell RNA sequencing; small hairpin RNA; spatiotemporal; transcriptomics

Project Summary Brown adipose tissue (BAT) is a specialized type of adipose that is primarily responsible for regulating body temperature. Once activated by cold, BAT dissipates the chemical energy as heat in a process called adaptive thermogenesis. Activating and expanding the thermogenic adipose tissue are attractive ways to increase energy expenditure and offer promising strategies to combat obesity and cardiometabolic diseases. A critical barrier to harnessing the potential of BAT to enhance cardiometabolic health in humans is the lack of understanding of the full range of pathways involved in the activation of BAT thermogenesis. Chronic cold exposure stimulates BAT thermogenesis through the coordinated stimulation of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are spatiotemporally coordinated is not known. Using single- cell transcriptomic analysis of BAT, we have recently identified the network of cellular interactome in the thermogenic adipose niche. This proposal is built on our recent discovery of Slit guidance ligand 3 (Slit3) as an essential regulator of BAT thermogenesis through controlling both angiogenesis and sympathetic innervation in BAT. This proposal examines the mechanisms by which Slit3 fragments stimulate vascular endothelial cells and sympathetic neurites to promote angiogenesis and sympathetic innervation. We hypothesize that the N-terminal and C-terminal fragments of Slit3 (Slit3-N and Slit3-C) bind to distinct receptors on endothelial cells and sympathetic nerves to stimulate angiogenesis and sympathetic innervation. In aim 1, we will use AAV-mediated gene delivery to overexpress Slit3 fragments in BAT and determine the effects of each fragment on angiogenesis and sympathetic innervation. In aim 2, we will use a panel of in vitro and in vivo models to identify the specific receptors responsible for mediating the effects of Slit3 fragments in vascular endothelial cells and sympathetic nerves. The proposed studies will provide a broad and deep understanding of how Slit3 regulates the two essential processes involved in BAT thermogenesis, angiogenesis, and sympathetic innervation. These studies will identify new potential nodes of intervention for obesity and metabolic diseases by stimulating the healthy expansion of thermogenic fat.

项目概要 棕色脂肪组织（BAT）是一种特殊类型的脂肪，主要负责调节身体 温度。一旦被寒冷激活，BAT 就会在称为适应性的过程中将化学能转化为热量 生热作用。激活和扩张产热脂肪组织是增加能量的有吸引力的方法 支出并提供对抗肥胖和心脏代谢疾病的有前景的策略。一个关键障碍 利用 BAT 的潜力来增强人类心脏代谢健康的原因是缺乏对 涉及 BAT 产热激活的全方位途径。长期接触寒冷会刺激 BAT 通过协调刺激棕色脂肪生成、血管生成和交感神经产生热量 神经支配。然而，这些不同的过程如何在时空上协调尚不清楚。使用单 通过对 BAT 的细胞转录组分析，我们最近发现了 BAT 中的细胞相互作用组网络 产热脂肪生态位。该提案建立在我们最近发现的狭缝引导配体 3 (Slit3) 的基础上 通过控制血管生成和交感神经支配来调节 BAT 生热作用 蝙蝠。该提案研究了 Slit3 片段刺激血管内皮细胞的机制以及 交感神经突促进血管生成和交感神经支配。我们假设 N 端 Slit3 的 C 端片段（Slit3-N 和 Slit3-C）与内皮细胞上的不同受体结合， 交感神经刺激血管生成和交感神经支配。在目标 1 中，我们将使用 AAV 介导的 基因递送以在 BAT 中过表达 Slit3 片段并确定每个片段对血管生成的影响 和交感神经支配。在目标 2 中，我们将使用一组体外和体内模型来识别特定的 负责介导 Slit3 片段在血管内皮细胞和交感神经细胞中的作用的受体 神经。拟议的研究将为 Slit3 如何调节这两者提供广泛而深入的理解。 涉及 BAT 产热、血管生成和交感神经支配的重要过程。这些研究 将通过刺激健康​​来确定干预肥胖和代谢疾病的新的潜在节点 产热脂肪的膨胀。