Differential expression and function of excitatory glutamate receptors across spinal cord anatomy, development, sex, and species

兴奋性谷氨酸受体在脊髓解剖、发育、性别和物种中的差异表达和功能

• 批准号: RGPIN-2020-07134
• 负责人: Hildebrand, Michael
• 金额: $ 2.33万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=718709
• 关键词: Differential; expression; function; excitatory; glutamate

The dorsal horn of the spinal cord is an essential component of the pain transmission pathway. Neurons in the outer layers of the dorsal horn receive incoming sensory information from the periphery, including pain-producing stimuli, and combine these signals with descending modulation from the brain. After combining and integrating these inputs, output neurons from the dorsal horn send processed pain signals up to brain pain centers. Changes in excitability within this dorsal horn neuronal network can lead to chronic pain, and yet even the basic electrical properties of these critical pain processing neurons remain incompletely understood. For example, the exact types of glutamate receptors that receive excitatory messages from the periphery and brain have not been explored. Moreover, what is known on excitatory neurotransmission in the dorsal horn is largely based on studies using male rodents. To develop better treatments for pain, foundational knowledge is required on what specific types of receptors shape dorsal horn pain processing across sex and species. To address this large translational gap, we will investigate the expression and function of excitatory glutamate receptors in subpopulations of dorsal horn neurons in both male and female rats as well as in humans. Through a unique collaboration with a neurosurgeon researcher at the Ottawa Hospital, Dr. Eve Tsai, our team is able to collect viable human spinal cord tissue from neurologic determination of death organ donors. Thus, we are one of a handful of labs in the world capable of exploring molecular determinants of pain processing in the human spinal cord. By combining complementary experimental approaches that include electrical recordings, protein staining, and single-cell RNA sequencing, we will systematically investigate how glutamate receptor expression and function changes across dorsal horn anatomy, development, sex and species. This information will shed light on how specific neuron types and signaling mechanisms can drive healthy pain sensation, and how molecular susceptibility to hyperexcitability and chronic pain may diverge between males and females as well as during aging. These discoveries will form the first steps towards identifying which pain-producing molecules are best suited as potential targets for new chronic pain treatments. The training of scientists throughout this research program will provide Canada with highly skilled workers equipped for careers in industrial, academic, health, and government professions. Given the novelty of our human tissue approaches, trainees in the lab will have opportunities to work alongside international research partners that are currently forming a major human tissue pain research consortium. These efforts will therefore increase Canada's competitiveness in a knowledge-based global economy.

脊髓背角是疼痛传递通路的重要组成部分。背角外层的神经元接收来自周围的感觉信息，包括产生疼痛的刺激，并将这些信号与来自大脑的下行调制结合起来。在结合和整合这些输入之后，来自背角的输出神经元将处理后的疼痛信号发送到脑疼痛中心。背角神经元网络兴奋性的变化可能导致慢性疼痛，然而这些关键的疼痛处理神经元的基本电特性仍然不完全清楚。例如，从外周和大脑接收兴奋性信息的谷氨酸受体的确切类型尚未被探索。此外，对背角兴奋性神经传递的了解主要是基于对雄性啮齿动物的研究。为了开发更好的疼痛治疗方法，需要了解不同性别和物种的特定类型的受体形成背角疼痛处理的基础知识。为了解决这一巨大的翻译空白，我们将研究兴奋性谷氨酸受体在雄性和雌性大鼠以及人类背角神经元亚群中的表达和功能。通过与渥太华医院神经外科研究员蔡伊芙博士的独特合作，我们的团队能够从死亡器官供者的神经学鉴定中收集有活力的人类脊髓组织。因此，我们是世界上少数几个能够探索人类脊髓疼痛处理的分子决定因素的实验室之一。通过结合互补的实验方法，包括电记录、蛋白质染色和单细胞RNA测序，我们将系统地研究谷氨酸受体的表达和功能如何在背角解剖、发育、性别和物种中发生变化。这一信息将阐明特定的神经元类型和信号机制如何驱动健康的痛觉，以及对高兴奋性和慢性疼痛的分子易感性如何在男性和女性之间以及在衰老过程中发生差异。这些发现将为确定哪些产生疼痛的分子最适合作为新的慢性疼痛治疗的潜在目标迈出第一步。在整个研究项目中对科学家进行培训，将为加拿大提供在工业、学术、卫生和政府部门工作的高技能工人。鉴于我们人体组织方法的新颖性，实验室的学员将有机会与国际研究伙伴一起工作，这些合作伙伴目前正在组建一个主要的人体组织疼痛研究联盟。因此，这些努力将提高加拿大在以知识为基础的全球经济中的竞争力。