Understanding spinal neuropeptide signaling in itch

了解瘙痒中的脊髓神经肽信号传导

• 批准号: 10619024
• 负责人: Tayler Sheahan
• 金额: $ 12.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619024
• 关键词: Acute; Address; Algorithmic Analysis; Anatomy; Award; Behavior; Behavioral; Bombesin Receptor; Code; Collaborations; Dedications; Dermatologist; Development; Disease; Education; Electron Microscopy; Excitatory Synapse; Gastrin releasing peptide; Glutamates; Goals; Health; Image; Knowledge; Label; Lead; Leadership; Learning; Left; Mentorship; Modeling; Mus; Nervous System; Neurons; Neuropeptides; Neurotransmitters; Pain Clinics; Pain Research; Pathologic; Patients; Peptide Signal Sequences; Phase; Population; Preparation; Pruritus; Quality of life; Research; Research Personnel; Rodent; Role; Signal Transduction; Skin; Spinal; Spinal Cord; Spinal cord posterior horn; Spinal nerve structure; Stimulus; Substance P; Synapses; Synaptic Transmission; TACR1 gene; Testing; Time; Training; Up-Regulation; Vertebral column; Visit; Visualization; Work; analysis pipeline; behavioral pharmacology; career; career development; career networking; chronic itch; effective therapy; experimental study; genetic approach; innovation; insight; machine learning algorithm; mouse model; neural; neural circuit; neuromechanism; neurotransmission; novel therapeutics; pharmacologic; programs; receptor; skills; somatosensory; success; symposium; training opportunity; transmission process; two-photon

PROJECT SUMMARY/ABSTRACT Chronic itch disorders are the primary reason for visits to dermatologists and have devasting effects on patient quality of life. Despite extensive research efforts, an effective treatment for chronic itch remains elusive, in part because the basic neural coding that underlies itch is poorly understood. The long-term goal of the investigator’s research program is to elucidate the neural mechanisms that underlie processing of itch input under normal and pathological conditions. Interestingly, one hallmark of chronic itch disorders is the upregulation of excitatory neuropeptides that drive itch – substance P (SP) and gastrin-releasing peptide (GRP) – within the spinal cord. However, the mechanism by which neuropeptides modulate spinal circuits to produce itch is unclear. To address this fundamental gap in knowledge, this proposal will investigate whether neuropeptides (SP and GRP) act in parallel with neurotransmitters (on the same targets) or if neuropeptide signaling diverges from neurotransmission (engage distinct targets), thereby reconfiguring spinal circuits. Specifically, the investigator will test the hypothesis that the itch-inducing neuropeptides SP and GRP act via divergent signaling to reconfigure neural circuits in acute and persistent itch. During the K99 Phase, she will learn and apply cutting- edge approaches that span from the neuron ultrastructural to population level. Aim 1 (K99) will compare spinal synaptic connectivity to neuropeptide connectivity using multiplexed electron microscopy. Aim 2 (K99) will identify the spinal networks activated by neuropeptide versus synaptic transmission from SP (and GRP) spinal neurons using two-photon Ca2+ imaging in combination with an ex vivo somatosensory preparation. A portion of the K99 phase will also be dedicated to learning to implement machine learning algorithms to detect and quantify mouse itch behaviors, and to career development activities such as gaining leadership and mentorship skills and presenting at conferences to expand the applicant’s professional network. Aim 3 (R00) will determine whether the SP and GRP signaling are required for the manifestation of aberrant spontaneous spinal cord activity (Aim 3A) and elevated itch behaviors (Aim 3B) associated with persistent itch using pharmacological inhibition strategies. These studies will leverage her new expertise in two-photon Ca2+ imaging and automated behavioral analysis pipelines developed during the K99 phase in combination with her strong background in rodent itch models. Together, these experiments will provide fundamental insights into neuropeptide signaling in spinal itch transmission and identify the necessity of spinal neuropeptide signaling in persistent itch. The success of this career award training plan, which includes activities for scientific and career development, will be aided by the scientific expertise, collaboration, and educational opportunities offered by the Pittsburgh Center for Pain Research. Completing this plan will prepare the applicant to lead an innovative research program as an independent investigator.

项目摘要/摘要 慢性瘙痒疾病是去皮肤科医生来访的主要原因，对患者产生破坏性的影响 生活质量。尽管进行了广泛的研究工作，但对慢性瘙痒的有效治疗仍然难以捉摸，部分原因是 因为瘙痒的基本神经编码知之甚少。调查员的长期目标 研究计划是为了阐明在正常和 病理状况。有趣的是，慢性瘙痒疾病的一个标志是兴奋的上调 在脊髓内驱动瘙痒的神经肽 - 物质P（SP）和胃蛋白释放肽（GRP）。 然而，神经肽调节脊柱回路的机制尚不清楚。解决 在知识上，这一建议将调查神经肽（SP和GRP）是否在 与神经递质（在同一靶标上）平行，或者神经肽信号传导与 神经传递（参与不同的靶标），从而重新配置脊柱回路。具体来说，研究人员 将检验以下假设，即瘙痒诱导的神经肽SP和GRP通过发散信号与 急性和持续性瘙痒中的中性电路重新配置。在K99阶段，她将学习和应用剪裁 - 从神经元超微结构到人群水平的边缘接近。 AIM 1（K99）将比较脊柱 使用多路复用电子显微镜与神经肽连接性的突触连通性。 AIM 2（K99）将 识别由SP（和GRP）脊柱激活的神经肽与突触传播激活的脊柱网络 使用两光子Ca2+成像的神经元与离体体感制剂结合使用。一部分 K99阶段还将致力于学习实施机器学习算法以检测和量化 鼠标瘙痒行为，以及职业发展活动，例如获得领导能力和精神技能和 在会议上展示申请人的专业网络。 AIM 3（R00）将确定是否 SP和GRP信号传导是需要异常的赞助脊髓活动所必需的（AIM 3A）和较高的瘙痒行为（AIM 3B）与使用药物抑制有关 策略。这些研究将利用她在两光子CA2+成像和自动化行为方面的新专业知识 分析管道在K99阶段开发，与她在啮齿动物瘙痒中的强烈背景相结合 型号。这些实验将共同提供对脊柱瘙痒中神经肽信号传导的基本见解 传递并确定持续瘙痒中脊柱神经肽信号的必要条件。这个成功 职业奖培训计划包括科学和职业发展活动，将由 匹兹堡痛苦中心提供的科学专业知识，协作和教育机会 研究。完成该计划将使申请人为领导创新研究计划做好准备 独立研究者。