The role of ENF loss, TLR4 and spinal plasticity in paclitaxel CIPN

ENF 缺失、TLR4 和脊柱可塑性在紫杉醇 CIPN 中的作用

• 批准号: 9271164
• 负责人: Patrick M Dougherty
• 金额: $ 47.99万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-09 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271164
• 关键词: Affect; Anatomy; Animals; Area; Astrocytes; Automobile Driving; Behavioral; Biochemical; Biopsy; Bortezomib; Cancer Patient; Cancer Survivor; Cell physiology; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Cisplatin; Clinical Trials; Data; Development; Distal; Distress; Dose-Limiting; Down-Regulation; Drops; Drug usage; Dysesthesias; Equipment and supply inventories; Glial Fibrillary Acidic Protein; Glutamate Transporter; Goals; Human; Immune; Infiltration; Innate Immune Response; Intervention; Lead; Malignant Neoplasms; Measures; Mechanics; Mechanoreceptors; Molecular; Natural Immunity; Nerve; Nerve Fibers; Neuroglia; Neurons; Neuropathy; Numbness; Paclitaxel; Pain; Patient risk; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Physiological; Prevention; Prevention strategy; Process; Productivity; Proteins; Quality of life; Rattus; Refractory; Rehabilitation therapy; Risk Factors; Role; Sensorimotor functions; Sensory; Signal Transduction; Skin; Spinal; Symptoms; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Translating; Vincristine; Work; cancer type; chemotherapy; curative treatments; density; disability; dorsal horn; follow-up; in vivo; insight; nerve supply; painful neuropathy; patient population; patient stratification; personalized medicine; prevent; public health relevance; reflectance confocal microscopy; response; spontaneous pain; success; volunteer

 DESCRIPTION (provided by applicant): Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. Chemotherapy-induced peripheral neuropathy (CIPN) is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivity. The continuing long-term goal of this project is to determine the mechanisms of CIPN and identify potential therapeutic interventions for its relief or prevention. The main hypothesis in this project is that chemotherapeutics activate toll-like receptor 4 (TLR4) on subsets of DRG neurons that 1) trigger altered cellular signaling in DRG neurons and infiltration of the DRG by immune cells that initiate and sustain CIPN; 2) drive the loss of distal epidermal nerve fibers (ENFs) to a critical point associated with onset of CIPN symptoms; and 3) cause activation of spinal glia and neurons that result in maladaptive changes in the physiology of these cells that further contribute to CIPN symptoms. This hypothesis will be tested in humans and animals that receive chemotherapy treatments. Specific Aim 1 will determine whether activation of innate immunity in the DRG is a key initiating step in CIPN. Specific Aim 2 will determine whether CIPN in humans is triggered when peripheral innervation density decreases to a critical point during chemotherapy. Specific Aim 3 will determine the role of TLR4 and damage associated molecular pattern (DAMP) proteins in driving maladaptive plasticity in the spinal dorsal horn contributing to CIPN. In summary this project will define mechanisms of chemotherapy-induced peripheral neuropathy, identify patient risk factors and potential new near-term protective and treatment candidates. This project will therefore impact on the quality of life, survival and the return to productivity of thousands of cancer patients.

 描述（由申请人提供）：周围神经病变是用于治疗所有最常见类型癌症的每种主要一线化疗药物的主要剂量限制因素，因此每年影响数十万患者。神经病变导致如此痛苦，许多患者将退出潜在的治疗，直接影响他们的生存。化疗诱导的周围神经病变（CIPN）是治疗难治性的，并且通常在癌症幸存者中持续存在，限制了生活质量，康复和恢复生产力。该项目的长期目标是确定CIPN的机制，并确定潜在的治疗干预措施，以缓解或预防CIPN。该项目中的主要假设是化疗剂激活DRG神经元亚群上的toll样受体4（TLR 4），其1）触发DRG神经元中改变的细胞信号传导和免疫细胞对DRG的浸润，所述免疫细胞启动和维持CIPN; 2）驱动DRG远端神经元的丢失，所述Toll样受体4（TLR 4）在DRG神经元的亚群上激活。 表皮神经纤维（ENF）至与CIPN症状发作相关的临界点;和3）引起脊髓神经胶质和神经元的活化，这导致这些细胞的生理学的适应不良变化，这进一步促成CIPN症状。这一假设将在接受化疗治疗的人类和动物中进行测试。特异性目标1将确定DRG中先天免疫的激活是否是CIPN的关键起始步骤。具体目标2将确定在化疗期间，当外周神经支配密度降低到临界点时，是否会触发人类的CIPN。具体目标3将确定TLR 4和损伤相关分子模式（DAMP）蛋白在驱动脊髓背角适应不良可塑性中的作用，从而导致CIPN。总之，本项目将确定化疗引起的周围神经病变的机制，确定患者的危险因素和潜在的新的近期保护和治疗候选人。因此，该项目将对成千上万癌症患者的生活质量、生存和恢复生产力产生影响。