Modulating somatosensory network to target metabolic diseases

摘要 监测内脏器官的新陈代谢状态对维持体内平衡至关重要，据信 主要由自主神经系统内的模糊神经调节。躯体感觉紧张 系统，其特征是驻留在背根神经节(DRG)的一级神经元簇，它是最好的 以其通过皮肤和皮肤在温度感觉、触觉、疼痛和本体感觉中的作用而闻名 肌肉学。新出现的证据表明，DRG神经元也大量投射到内脏，但它们的 由于缺乏足够的工具，人们对结构和生理功能的了解仍然很少 靶向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，我们提出了一个系统和专注的 努力开发专门为哺乳动物周围神经设计的变革性技术 能够对全身感觉网络进行光学成像、神经支配目标定义的分子的系统 侧写和器官特有的感觉神经调节。这项提案的目标是利用这些 体感神经回路的结构、分子和功能基础研究进展 新陈代谢器官，我们将用它来检验内部躯体感觉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的动态平衡，而这 特异性是由器官靶向DRG独特的拓扑和分子特性决定的 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 独特的，但历史上被低估的感觉网络支配脂肪组织。我们将首先测试是否肥胖- 在新陈代谢挑战时，背根神经节神经元正在传递特定的信号，以及这是否 传播对于维持全身的动态平衡很重要。归根结底，知识和专业知识 从最初的以脂肪为中心的努力中获得的成果将作为扩展我们对感官的询问的路线图 所有代谢器官的回路，并将带来潜在的革命性的战略，以治疗代谢紊乱。 该提案是一个雄心勃勃、具有潜在变革性、创新性的计划，非常适合新的 创新者奖，因为它打破了传统领域的壁垒，建立了神经生物学的新前沿：第一，充分 对内部体感网络的揭示可能会通过挑战传统的 外部感觉和内部感觉之间的区分。第二，这项建议的一大目标是发展长期的-- 为周围神经系统设计的期待的电路工具，它可能会有更广泛的 通过提供一种通用的、适应性的和强大的策略来研究周围神经，从而对该领域产生影响 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的一个新的令人兴奋的领域。

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.