Modulating somatosensory network to target metabolic diseases

摘要 监测内部器官的代谢状态对于维持体内平衡是至关重要的，并且被认为是 主要由自主神经系统内的模糊神经介导。躯体感觉神经 系统，其特征在于位于背根神经节（DRG）中的一级神经元簇， 已知其在通过皮肤的温度感觉、触觉感知、疼痛和本体感觉中的作用， 肌肉组织新出现的证据表明，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， 靶向外周感觉神经的特异性和功效。 凭借我们在神经技术和代谢方面的独特背景，我们提出了一个系统和集中的 努力开发专门为哺乳动物外周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的系统 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 技术，以解开结构，分子和功能基础的躯体感觉电路支配 代谢器官，我们将测试中心假设，内部体感网络是至关重要的 用于通过感测器官特异性代谢状态来维持全身代谢稳态，并且 特异性由靶向器官的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， 不同的，但历史上未得到充分重视的感觉网络支配脂肪组织。我们先测试一下脂肪- 在代谢挑战时，DRG神经元传递特定的信号， 传递对于维持全身内环境稳定是重要的。最终，知识和专业知识 从这一最初的脂肪集中的努力获得的将作为一个路线图，以扩大我们的感官审问， 这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的，具有潜在变革性的创新计划，非常适合新的 创新者奖，因为它打破了传统领域的障碍，建立了神经生物学的新前沿：第一，充分 内部躯体感觉网络的揭示可以通过挑战传统的 外感觉和内感觉之间的区别。第二，这一建议的一个主要目标是发展长期- 为周围神经系统设计的期待已久的电路工具，这将可能具有更广泛的 通过提供一种通用的，自适应的，强大的策略来研究周围神经系统， 系统最后，这个项目独特地利用了我在神经技术，分子生物学， 生物学和代谢，率先探索神经生物学和生理学的一个新的激动人心的领域。

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.