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.

项目摘要 棕色脂肪组织（BAT）是一种专门的脂肪，主要负责调节身体 温度。一旦被冷激活，BAT在称为自适应的过程中将化学能作为热量消散 热发生。激活和扩展热脂肪组织是增加能量的有吸引力的方法 支出并提供有前途的策略来打击肥胖和心脏代谢疾病。一个关键的障碍 利用蝙蝠在人类中增强心脏代谢健康的潜力是缺乏对 蝙蝠热发生激活涉及的全范围途径。慢性冷暴露会刺激蝙蝠 通过协调刺激棕色脂肪生成，血管生成和交感神经的热生成 神经。但是，这些不同的过程是如何在空间时置协调的。使用单个 BAT的细胞转录组分析，我们最近确定了细胞相互作用的网络 热脂肪生态位。该提议建立在我们最近发现的缝隙指南3（slit3）作为 通过控制血管生成和交感神经的基本调节剂的基本调节剂 蝙蝠。该建议研究了裂缝3片段刺激血管内皮细胞和 促进血管生成和交感神经的交感神经突。我们假设N末端 slit3（slit3-n和slit3-c）的C末端片段与内皮细胞和内皮细胞上的不同受体结合 刺激血管生成和交感神经的交感神经。在AIM 1中，我们将使用AAV介导的 基因递送到BAT中的过表达SLIT3片段，并确定每个片段对血管生成的影响 和同情神经。在AIM 2中，我们将使用一组体外和体内模型来识别特定 负责介导SLIT3片段在血管内皮细胞和交感神经中的影响的受体 神经。拟议的研究将对Slit3如何调节两者提供广泛而深刻的了解 与BAT热生成，血管生成和交感神经有关的基本过程。这些研究 通过刺激健康​​的肥胖和代谢疾病的干预措施的新潜在节点 热脂肪的膨胀。