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 监测内脏器官的代谢状态对于维持体内平衡至关重要，并且被认为是 主要由自主神经系统内的模糊神经介导。体感神经 系统，其特征是位于背根神经节（DRG）的一级神经元簇，最好 因其在皮肤和触觉的热感觉、触觉、疼痛和本体感觉中的作用而闻名。 肌肉组织。新的证据表明 DRG 神经元也大量投射到内脏器官，但它们的 由于缺乏足够的工具，结构和生理功能仍然知之甚少。 针对周围感觉神经的特异性和有效性。 凭借我们在神经技术和新陈代谢方面的独特背景，我们提出了系统性和有针对性的 努力开发专为哺乳动物周围神经设计的变革性技术 系统能够实现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。该提案的目标是利用这些 揭示体感神经回路的结构、分子和功能基础的技术 代谢器官，我们将用它来检验内部体感网络至关重要的中心假设 通过感知器官特定的代谢状态来维持全身代谢稳态，这 特异性由靶向器官 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了一种形态致密的分子 支配脂肪组织的独特但历史上未被充分认识的感觉网络。我们将首先测试是否肥胖- DRG 神经元在代谢挑战时会传递特定信号，以及这是否 传播对于维持全身稳态很重要。最终，知识和专业知识 从最初以脂肪为中心的努力中获得的成果将作为扩大我们对感官的询问的路线图 电路连接所有代谢器官，将为治疗代谢紊乱带来潜在的革命性策略。 该提案是一项雄心勃勃、具有潜在变革性的创新计划，非常适合新时代 创新奖打破传统领域壁垒，建立神经生物学新前沿：一是全面 内部体感网络的揭示可能会通过挑战传统的方式来改变范式 外感受和内感受的区别。其次，本提案的一个主要目标是发展长期 期待为周围神经系统设计的电路工具，它可能有更广泛的应用 通过提供通用、适应性和强大的策略来研究周围神经，对该领域产生影响 系统。最后，这个项目独特地利用了我在神经技术、分子技术等方面的跨学科专业知识 生物学和新陈代谢，带头探索神经生物学和生理学这一令人兴奋的新领域。