Targeting checkpoint inhibitors for pain control

针对疼痛控制的检查点抑制剂

基本信息

批准号：
10771904
负责人：
RU-RONG JI
金额：
$ 256.99万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10771904
关键词：
3-Dimensional AVIL gene Absence of pain sensation Acute Afferent Neurons Analgesics Autoimmunity Behavior Binding Bone Pain Cancer Patient Capsaicin Carrageenan Cells Disease Electrophysiology (science)FDA approved Goals Human Hyperalgesia Immune Immune Targeting Immune checkpoint inhibitor Immunity Immunotherapy Inflammatory Inflammatory Response Knock-out Knockout Mice Macaca mulatta Macrophage Malignant Bone Neoplasm Malignant Neoplasms Manuals Measures Mechanics Mediating Metastatic Neoplasm to the Bone Microglia Monoclonal Antibodies Morphine Mus Neurons Neuropathy Nivolumab Nociception Opioid Opioid Analgesics Osteoclasts PD-1 pathway Pain Pain Threshold Pain management Pathologic Pathway interactions Patients Physiological Postoperative Pain Postoperative Period Proteins Regulation Reporter Reporting Rewards Role Signal Transduction Slice Spinal Cord Spinal Ganglia System T-Lymphocyte Testing abuse liability anti-PD1 therapy antinociception bone cancer pain carcinogenesis cell type conditional knockout cytokine excitatory neuron immune checkpoint inflammatory pain inhibitor inhibitory neuron insight monocyte mouse model neuroinflammation neuronal excitability neurotransmission nonhuman primate novel pain sensitivity painful neuropathy programmed cell death ligand 1 programmed cell death protein 1 receptor side effect spontaneous pain

3-Dimensional AVIL gene Absence of pain sensation Acute Afferent Neurons Analgesics Autoimmunity Behavior Binding Bone Pain Cancer Patient Capsaicin Carrageenan Cells Disease Electrophysiology (science)FDA approved Goals Human Hyperalgesia Immune Immune Targeting Immune checkpoint inhibitor Immunity Immunotherapy Inflammatory Inflammatory Response Knock-out Knockout Mice Macaca mulatta Macrophage Malignant Bone Neoplasm Malignant Neoplasms Manuals Measures Mechanics Mediating Metastatic Neoplasm to the Bone Microglia Monoclonal Antibodies Morphine Mus Neurons Neuropathy Nivolumab Nociception Opioid Opioid Analgesics Osteoclasts PD-1 pathway Pain Pain Threshold Pain management Pathologic Pathway interactions Patients Physiological Postoperative Pain Postoperative Period Proteins Regulation Reporter Reporting Rewards Role Signal Transduction Slice Spinal Cord Spinal Ganglia System T-Lymphocyte Testing abuse liability anti-PD1 therapy antinociception bone cancer pain carcinogenesis cell type conditional knockout cytokine excitatory neuron immune checkpoint inflammatory pain inhibitor inhibitory neuron insight monocyte mouse model neuroinflammation neuronal excitability neurotransmission nonhuman primate novel pain sensitivity painful neuropathy programmed cell death ligand 1 programmed cell death protein 1 receptor side effect spontaneous pain

展开

项目摘要

Abstract Emerging immunotherapy has shown efficacy for patients with various cancers. Targeting the immune checkpoint proteins, such as programmed cell death protein-1 ligand 1 (PD-L1) and its receptor PD-1 using monoclonal antibodies has saved lives of cancer patients. PD-L1 was thought to suppress immunity via binding to PD-1 receptor on T cells. Immunotherapies also produce side effects by increasing autoimmunity. We recently reported that PD-1 is also expressed by neurons (e.g., dorsal root ganglia primary sensory neurons and spinal cord neurons) and macrophages/osteoclasts, but the function of PD-1 in these cell types remains to be validated using specific lines of Pd1 conditional knockout (cKO) mice. The goal of this study is to investigate how the PD- L1/PD-1 checkpoint pathway controls physiological and pathological pain and opioid analgesia via neuronal, immune, and glial mechanisms. To determine the cellular mechanisms of PD-1’s actions, we will use conditional knockout mice (cKO), with selective deletion of Pd1 in sensory neurons, microglia, and macrophages, to test the following hypotheses and specific aims. Aim 1: Test the hypothesis that PD-L1/PD-1 cascade controls physiological pain and opioid analgesia in non-injured mice; Aim 2: Test the hypothesis that PD-L1/PD-1 cascade regulates inflammatory, postoperative, neuropathic, and bone cancer pain via neuronal, immune, and microglial signaling in mice; Aim 3: Validate the actions of PD-L1 and nivolumab on neuroinflammation or/and pain in NHPs and in human DRG. Successful completion of this project will validate an important role of PD-L1/PD-1 axis in pain control. This study will also provide novel insights into distinct actions of checkpoint pathway activators and inhibitors for the management of different types of pain (inflammatory/postoperative/neuropathic pain vs. bone cancer pain).

抽象的新兴的免疫疗法显示出对各种癌症患者的效率。靶向免疫检查点蛋白，例如使用编程的细胞死亡蛋白1配体1（PD-L1）及其接收器PD-1 单克隆抗体挽救了癌症患者的生命。 PD-L1被认为可以通过结合抑制免疫学到T细胞上的PD-1受体。免疫疗法还通过增加自身免疫性产生副作用。我们最近据报道，PD-1也由神经元（例如背根神经节前感觉神经元和脊柱表达脐带神经元）和巨噬细胞/破骨细胞，但是PD-1在这些细胞类型中的功能仍有待验证使用特定的PD1条件敲除（CKO）小鼠。这项研究的目的是研究PD- L1/PD-1检查点途径通过神经元控制身体和病理疼痛，阿片类镇痛，免疫和神经胶质机制。为了确定PD-1动作的细胞机制，我们将使用条件敲除小鼠（CKO），在感觉神经元，小胶质细胞和巨噬细胞中有选择性删除PD1，以测试遵循假设和特定目标。目标1：检验PD-L1/PD-1级联控制的假设无伤小鼠的生理疼痛和阿片类镇痛； AIM 2：检验PD-L1/PD-1级联的假设通过神经元，免疫和小胶质细胞调节炎症，术后，神经性和骨癌疼痛小鼠的信号传导； AIM 3：验证PD-L1和Nivolumab对NHP中神经炎症或/和疼痛的作用和人类的drg。成功完成该项目将验证PD-L1/PD-1轴的重要作用疼痛控制。这项研究还将为检查点途径激活剂和治疗不同类型疼痛的抑制剂（炎症/术后/神经性疼痛与骨骼癌症疼痛）。