Neuron-macrophage interactions in models of chemotherapy-induced peripheral neuropathy

化疗引起的周围神经病变模型中神经元-巨噬细胞的相互作用

基本信息

批准号：
10673851
负责人：
Wesley B Grueber
金额：
$ 18.84万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673851
关键词：
Affect Afferent Neurons Animal Model Animals Anti-Inflammatory Agents Astrocytes Biological Response Modifiers Cells Chemotherapy-induced peripheral neuropathy Chronic Clinic Coculture Techniques Data Detection Drosophila genus Environment Gene Targeting Genes Health Host Defense Human Hypersensitivity Immune In Situ In Vitro Infiltration Inflammation Inflammatory Knowledge Link Macrophage Macrophage Activation Maps Mediating Modeling Molecular Profiling Monitor Morphology Mus Natural regeneration Nature Nerve Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nociception Nociceptors Paclitaxel Pain Pathogenesis Pathologic Pathway interactions Patients Peripheral Persons Phenotype Prevention Prevention strategy Proteins Publishing Recombinants Research Role Sensory Skin Spinal Ganglia Supplementation System Testing Therapeutic Time Toxic effect Treatment-related toxicity Up-Regulation Work cell type chemotherapy clinically relevant cytokine debilitating pain deep learning effective therapy extracellular genetic manipulation immunoregulation in vivo in vivo Model innovation mouse model nerve injury neuronal survival neurotoxicity neurotrophic factor overexpression pain sensitivity painful neuropathy prevent sensory neuropathy treatment strategy

项目摘要

Summary/Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) affects over 3 million people in the US without effective treatment. CIPN predominantly affects nociceptive (pain-sensing) nerve terminals, and often manifests as chronic debilitating pain in patients. Chemotherapy-induced inflammation strongly correlates with the onset of and persistent neuropathic pain. We propose to investigate peripheral interactions between macrophages, the most abundant immune cell type residing in skin, and nociceptive nerve terminals in CIPN. Molecular profiles of macrophages change continuously depending on their extracellular environment, allowing them to transition from resident to activated states. While pro- and anti-inflammatory activation of macrophages has been extensively studied, recent studies revealed many intermediate forms during the transition. How these are linked to pathological progression of nerves is still poorly understood, and we propose to fill this gap by using two complementary systems, Drosophila and mouse CIPN models. We will test the hypothesis that modulating macrophage activation could prevent peripheral sensory neuron hypersensitivity in CIPN. In our preliminary work, we established a Drosophila model to study neuron-macrophage interaction in vivo and found that macrophages activate and transition into different intermediate forms in a time-dependent manner that corresponds to nociceptive neuron phenotypes. Leveraging a single-cell quantitative approach using deep learning cell detection in situ, we found that expansion of activated macrophages peaks preceding morphological degeneration of neurons with a robust increase in selected pro- and anti-inflammatory genes. We further found a significant reduction in anti-inflammatory macrophages at a later stage, indicating an immune state switch between intermediate and late pathological stages. In search of genes that could modulate macrophage activation to promote neuronal health while not interfering with their roles in host defense, we identified mesencephalic astrocyte-derived neurotrophic factor, MANF, as a potential gene target for CIPN prevention. MANF is a potent regulator of immune activity, and its overexpression reduces the pro-inflammatory pathway and promotes activation of the anti-inflammatory pathway. In support, our preliminary results demonstrate that augmenting MANF prevents neuron phenotypes in Drosophila and mouse CIPN models, consistent with our hypothesis. We propose to characterize chemotherapy-induced macrophage profiles and investigate how MANF modulates macrophages to prevent neuronal toxicity in Drosophila in vivo and mouse neuron-macrophage co- culture CIPN models. Our proposal has a high potential to contribute to effective anti-inflammatory treatment for promoting neuronal health in CIPN.

摘要/摘要：化疗引起的周围神经病变 (CIPN) 在美国影响着超过 300 万人，但没有有效的治疗方法治疗。 CIPN 主要影响伤害性（疼痛感觉）神经末梢，通常表现为使患者遭受慢性衰弱性疼痛。化疗引起的炎症与癌症的发生密切相关和持续的神经性疼痛。我们建议研究巨噬细胞之间的外周相互作用，最丰富的免疫细胞类型存在于皮肤和 CIPN 中的伤害性神经末梢中。分子概况巨噬细胞根据其细胞外环境不断变化，使它们能够从驻留在激活状态。虽然巨噬细胞的促炎和抗炎激活作用已被广泛研究经过研究，最近的研究揭示了过渡期间的许多中间形式。这些是如何链接到的神经的病理进展仍然知之甚少，我们建议通过使用两种方法来填补这一空白互补系统、果蝇和小鼠 CIPN 模型。我们将测试调节的假设巨噬细胞激活可以预防 CIPN 中的周围感觉神经元过敏。在我们的前期工作中，我们建立了果蝇模型来研究体内神经元-巨噬细胞的相互作用，并发现巨噬细胞以时间依赖性方式激活并转变为不同的中间形式对应于伤害性神经元表型。利用深度单细胞定量方法通过原位学习细胞检测，我们发现活化巨噬细胞的扩张在形态学之前达到峰值神经元退化，选定的促炎和抗炎基因大幅增加。我们进一步发现后期抗炎巨噬细胞显着减少，表明免疫状态转换介于病理中期和晚期之间。寻找可以调节巨噬细胞的基因激活以促进神经元健康，同时不干扰它们在宿主防御中的作用，我们发现中脑星形胶质细胞衍生的神经营养因子 (MANF) 作为 CIPN 预防的潜在基因靶标。 MANF 是免疫活性的有效调节剂，其过度表达会减少促炎途径并促进抗炎途径的激活。作为支持，我们的初步结果表明增强 MANF 可防止果蝇和小鼠 CIPN 模型中的神经元表型，这与我们的研究一致假设。我们建议表征化疗诱导的巨噬细胞谱并研究 MANF 如何调节巨噬细胞以防止果蝇体内神经元毒性和小鼠神经元-巨噬细胞协同作用文化 CIPN 模型。我们的建议很有可能为有效的抗炎治疗做出贡献促进 CIPN 中的神经元健康。