Foundational tools to study the impacts of sympathetic activity on the neuroanatomy and function of brown adipose tissue

研究交感神经活动对棕色脂肪组织神经解剖学和功能影响的基础工具

• 批准号: 9981855
• 负责人: Lori M Zeltser
• 金额: $ 25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-28 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981855
• 关键词: Adipose tissue; Adrenergic Fibers; Adult; Afferent Neurons; Anesthetics; Animals; Autopsy; Axon; Basal metabolic rate; Biological Assay; Brain; Brown Fat; Cadaver; Chronic; Complex; Efferent Neurons; Electrons; Fiber; Forelimb; Foundations; Future; Ganglia; Genetic; Goals; Heart; Heart Diseases; Histologic; Hot flushes; Human; Image; Impairment; Knowledge; Label; LacZ Genes; Lead; Maps; Measurement; Measures; Menopause; Metabolic; Methods; Microscopic; Mitochondria; Molecular; Mus; Nerve; Neuroanatomy; Neurons; Neurotransmitters; Obesity; Operative Surgical Procedures; Organ; Organ Donor; Pain; Patients; Pattern; Peptides; Peripheral; Pharmacology; Physiological; Play; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Protocols documentation; Publishing; Refractory; Reporter; Reporting; Research; Rodent; Role; Sampling; Sensory; Severities; Side; Signal Transduction; Source; Spatial Distribution; Specimen; Stimulus; Structure of stellate ganglion; Supraclavicular; Sympathetic Ganglia; Sympathetic Nervous System; Syndrome; System; Techniques; Therapeutic; Thermogenesis; Three-Dimensional Imaging; Tissue Sample; Tissues; Tracer; Transcript; Transgenic Mice; Translating; Upper Extremity; Ventricular Tachycardia; Woman; biomarker identification; body system; candidate marker; clinical application; design; experimental study; field study; genetic approach; human tissue; in vivo; minimally invasive; molecular marker; mouse model; nerve supply; neural circuit; neuronal cell body; neuroregulation; pre-clinical; relating to nervous system; retrograde transport; theories; tool

PROJECT SUMMARY A growing body of evidence supports the idea that brown/beige adipose tissue (BAT) contributes to basal metabolism in adult humans, and that diminished BAT activity can lead to obesity. Sympathetic nerve stimulation increases BAT activity in rodents. Reports that signaling from the stellate ganglion (SG) modulates thermogenesis in humans, raises the possibility that minimally-invasive approaches to stimulate sympathetic projections from the SG to supraclavicular BAT (scBAT) have potential as an anti-obesity therapy. The neuroanatomy of the SG is complex, because sympathetic and sensory neuronal axons leave the ganglion through 6-8 different exit points to reach a wide variety of targets in the periphery. For neuromodulation of SG projections to BAT to have clinical applications, it is essential that stimulation protocols avoid projections from the SG to the heart and upper extremities. In theory, this can be achieved by physically focusing the electrical stimulus to SG neurons as they exit the SG or enter the scBAT depot. Alternatively, genetic approaches could be used restrict pharmacological manipulations to the subpopulation of SG neurons that innervates BAT. These complementary studies in mouse models and human tissue samples will serve as the basis for deciding which of these strategies are viable therapeutic options. The proposed studies are designed to fill critical information gaps and to develop tools needed for comprehensive mapping of neural circuits regulating BAT and to explore the potential use of BAT neuromodulation as an anti- obesity therapy. Studies in Aim 1 will use combinations of transgenic mouse models and fluorescent neuronal tracers to determine whether there is any physical overlap between BAT and forelimb-projecting soma within the SG or their exit points out of the SG. In parallel, we will perform the first mapping studies of the projections from the SG to scBAT in human autopsy specimens. A major obstacle to studies to modulate or record neural activity in the SG is that this ganglion contains many different types of afferent and efferent neurons that regulate a wide range of physiological functions. Studies in Aim 2 will define molecular markers for distinct subpopulations of SG neurons that project to BAT and heart. Then we will determine whether any of these markers are conserved in human surgical samples. Finally, studies in Aim 3 will establish systems to evaluate the impact of neuromodulation on the organization of sympathetic fibers in conjunction with well-established assays to measure BAT oxidative capacity and activity. To aid these efforts, we will develop techniques to image sympathetic projections in an intact BAT depot. In addition, we will validate key in vivo assays needed to assess the impacts of neuromodulation on BAT function that can be readily translated to humans. In addition to impacts on the BAT field, these studies will also provide a strong foundation for future efforts to understand how existing SG neuromodulation therapies have beneficial effects on a wide range of conditions that are refractory to other treatments, including ventricular tachycardia, chronic regional pain syndrome and post-traumatic stress disorder.

项目总结 越来越多的证据支持这样的观点，即棕色/米色脂肪组织(BAT)有助于 成年人的新陈代谢，这种蝙蝠活动减少会导致肥胖。交感神经刺激 增加啮齿动物的蝙蝠活动。报道来自星状神经节(SG)的信号调制 人类的产热作用，增加了微创刺激交感神经的可能性 从SG到锁骨上BAT(ScBAT)的投射具有抗肥胖治疗的潜力。这个 SG的神经解剖学很复杂，因为交感和感觉神经元轴突离开神经节。 通过6-8个不同的出口点到达外围的各种目标。对脑白质的神经调节作用 为了使BAT具有临床应用价值，刺激方案必须避免来自 心脏和上肢的SG。从理论上讲，这可以通过物理聚焦电子设备来实现 当它们离开SG或进入scBAT仓库时，对SG神经元进行刺激。或者，遗传方法可以 被用来限制对支配蝙蝠的SG神经元亚群的药理操作。这些 对小鼠模型和人类组织样本的互补性研究将作为决定哪种 这些策略中有许多是可行的治疗方案。 拟议的研究旨在填补关键信息空白，并开发必要的工具，以全面 绘制调节BAT的神经回路图，并探索BAT神经调节作为抗心绞痛的潜在用途 肥胖症治疗。AIM 1的研究将使用转基因小鼠模型和荧光神经元的组合 确定蝙蝠和前肢之间是否有任何物理重叠的示踪剂 SG或他们的退出点出了SG。与此同时，我们将对来自以下地点的预测进行第一次地图研究 在人类尸检标本中的SG到scBAT。研究调节或记录神经活动的主要障碍 在SG中，这个神经节包含许多不同类型的传入和传出神经元，它们调节着广泛的 生理功能的范围。AIM 2的研究将为SG的不同亚群定义分子标记 投射到蝙蝠和心脏的神经元。然后我们将确定这些标记中是否有任何标记在 人体手术样本。最后，目标3中的研究将建立系统来评估 交感神经纤维组织的神经调节与成熟的分析相结合 测量蝙蝠的氧化能力和活性。为了帮助这些努力，我们将开发技术来成像 在一个完整的蝙蝠仓库里有令人同情的预测。此外，我们将验证评估所需的关键体内分析 神经调节对蝙蝠功能的影响可以很容易地转化为人类。除了影响之外 在蝙蝠领域，这些研究也将为今后了解现有的 SG神经调节疗法对其他疾病难以治愈的多种疾病都有有益的效果 治疗包括室性心动过速、慢性区域疼痛综合征和创伤后应激障碍。