Modulating somatosensory network to target metabolic diseases

调节体感网络靶向代谢疾病

• 批准号: 10002554
• 负责人: Li Ye
• 金额: $ 266.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10002554
• 关键词: Adipose tissue; Area; Autonomic nervous system; Award; Characteristics; Development; Fatty acid glycerol esters; Foundations; Goals; Homeostasis; Interoception; Knowledge; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Biology; Molecular Profiling; Monitor; Morphology; Nerve; Nervous system structure; Neurobiology; Neurons; Organ; Pain; Perception; Peripheral; Peripheral Nervous System; Physiological; Physiology; Proprioception; Role; Sense Organs; Sensory; Signal Transduction; Skin; Specificity; Spinal Ganglia; Structure; Technology; Testing; Touch sensation; afferent nerve; design; frontier; innovation; neuroregulation; neurotechnology; optical imaging; programs; somatosensory; tool; transmission process; whole body imaging

Abstract Monitoring the metabolic states of internal organs is crucial for maintaining homeostasis and is believed to be primarily mediated by the vague nerve within the autonomic nervous system. The somatosensory nervous system, characterized by clusters of first-order neurons which reside in the dorsal root ganglia (DRG), it is best known for its role in thermosensation, touch perception, pain, and proprioception through the skin and musculature. Emerging evidence suggests DRG neurons also heavily project to internal organs, but their structures and physiological functions remain much less understood due to the lack of tools with adequate specificity and efficacy to target peripheral sensory nerves. With our unique background in both neurotechnology and metabolism, we propose a systemic and focused effort to develop transformative technologies specifically designed for the mammalian peripheral nervous system to enable optical imaging of whole-body sensory network, innervating target-defined molecular profiling, and organ-specific sensory neuromodulation. The goal of this proposal is to leverage these technologies to unravel the structural, molecular and functional basis of the somatosensory circuitry innervating metabolic organs, with which we will test the central hypothesis that internal somatosensory network is critical for maintaining whole-body metabolic homeostasis by sensing organ-specific metabolic states, and this specificity is determined by the unique topological and molecular characteristics of organ-targeting DRG neurons. A striking finding of our preliminary study was the discovery of a morphologically dense, molecularly distinct, yet historically under-appreciated sensory network innervating adipose tissues. We will first test if fat- specific signals are being conveyed by the DRG neurons upon metabolic challenges and whether this transmission is important for maintaining whole-body homeostasis. Ultimately, the knowledge and expertise gained from this initial fat-focused endeavor will serve as a roadmap to expand our interrogation of sensory circuitry to all metabolic organs and will bring potentially revolutionary strategies to treat metabolic disorders. This proposal is an ambitious, potentially transformative, innovative program ideally suited for the New Innovator Award as it breaks traditional field barriers to establish a new frontier of neurobiology: First, the full revelation of the internal somatosensory network could be paradigm-shifting by challenging the conventional division between exteroception and interoception. Second, a major goal of this proposal is to develop the long- awaited circuit tools designed for the peripheral nervous system, which would potentially have a broader impact on the field by providing a universal, adaptive, and powerful strategy to study the peripheral nervous system. Finally, this project uniquely leverages my interdisciplinary expertise in neurotechnology, molecular biology, and metabolism to spearhead the exploration of a new exciting area of neurobiology and physiology.

抽象的 监测内部器官的代谢状态对于维持稳态至关重要，据信是 主要是由自主神经系统中模糊神经介导的。体感紧张 系统，其特征是位于背根神经节（DRG）的一阶神经元群 以其在皮肤中以及 肌肉。新兴的证据表明，DRG神经元也大量投射到内部器官，但它们 由于缺乏足够的工具，结构和生理功能的理解程度要少得多 针对周围感觉神经的特异性和功效。 我们在神经技术和新陈代谢方面具有独特的背景，我们提出了一种系统性的专注 努力开发专门为哺乳动物外周神经设计的变革性技术 系统以启用全身感觉网络的光学成像，支配目标定义的分子 分析和器官特异性感觉神经调节。该提议的目的是利用这些 揭示体感电路支配的结构，分子和功能基础的技术 代谢器官，我们将通过其检验中心假设，即内部体感网络至关重要 通过感测特异性的代谢状态来维持全身代谢稳态，这 特异性由靶向器官靶向DRG的独特拓扑和分子特征决定 神经元。我们初步研究的一个惊人发现是发现形态密集的，分子 独特但历史悠久的感觉网络支配脂肪组织。如果脂肪 - 我们将首先测试 DRG神经元在代谢挑战方面传达了特定的信号 传输对于维持全身稳态很重要。最终，知识和专业知识 从最初以脂肪为重点的努力中获得的将作为扩展我们感官询问的路线图 向所有代谢器官进行电路，并将带来潜在的革命性策略来治疗代谢疾病。 该提议是一个雄心勃勃的，具有变革性的创新计划，非常适合新的 创新者奖破坏了传统的现场障碍以建立神经生物学的新领域：首先，完整 内部体感网络的启示可能是通过挑战常规的范式转移的 外部感受与际观察之间的分裂。第二，该提议的主要目标是开发长期 已久的电路工具为外围神经系统设计，该工具可能会更广泛 通过提供一种普遍，适应性和强大的策略来研究周围神经，对现场的影响 系统。最后，这个项目独特地利用了我的神经技术跨学科专业知识，分子 生物学和代谢，以探索神经生物学和生理学的新令人兴奋的领域。