Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3

项目摘要 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就会在一个称为适应性的过程中将化学能转化为热量 产热作用激活和扩大产热脂肪组织是增加能量的有吸引力的方法 这是一项非常有前景的战略，旨在防治肥胖症和心脏代谢疾病。一个关键的障碍， 利用BAT的潜力来增强人类的心脏代谢健康是缺乏对 参与BAT产热激活的全方位途径。慢性冷暴露刺激BAT 通过协调刺激棕色脂肪生成、血管生成和交感神经系统的产热 神经支配然而，这些不同的过程是如何时空协调是未知的。使用单- BAT的细胞转录组学分析，我们最近已经确定了细胞相互作用组网络， 产热脂肪生态位这个建议是建立在我们最近发现的狭缝导向配体3（Slit 3）作为一个 通过控制血管生成和交感神经支配， 球棒该提案研究了Slit 3片段刺激血管内皮细胞的机制， 交感神经突起以促进血管生成和交感神经支配。我们假设N-末端 和Slit 3的C-末端片段（Slit 3-N和Slit 3-C）与内皮细胞上的不同受体结合， 交感神经以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Slit 3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aim 2中，我们将使用一组体外和体内模型来鉴定特异性的 负责介导血管内皮细胞和交感神经细胞中Slit 3片段作用的受体 神经拟议的研究将提供一个广泛和深入的了解如何Slit 3调节这两个 参与BAT产热、血管生成和交感神经支配的基本过程。这些研究 将通过刺激健康， 产热脂肪的膨胀。

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.