Spinal cord stimulation for the attenuation of chemotherapy-induced peripheral neuropathy and enhanced chemotherapeutic efficacy

脊髓刺激可减轻化疗引起的周围神经病变并增强化疗效果

• 批准号: 10652410
• 负责人: Eellan Sivanesan
• 金额: $ 28.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652410
• 关键词: Acceleration; Aftercare; American Society of Clinical Oncology; Amyloid beta-Protein; Anesthesiology; Attenuated; Biology; Blood Vessels; C Fiber; Calcium; Cancer Biology; Cancer Survivor; Cell Proliferation; Chemotherapy-induced peripheral neuropathy; Clinical; Clinical Trials; Coupled; Data; Development; Dose; Dose Limiting; Electric Stimulation; Electrophysiology (science); Environment; Evaluation; Exposure to; Foundations; Funding; Future; Glioma; Goals; Human; Image; Immune; Immunology; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Injury; Instruction; Investigation; Knowledge; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Mediator; Mentors; Mentorship; Modality; Modeling; Motor; Neuroimmune; Neuroimmunomodulation; Neurons; Neurosciences; Neurostimulation procedures of spinal cord tissue; Nociception; Non-Small-Cell Lung Carcinoma; Paclitaxel; Pain; Pain management; Patient-Focused Outcomes; Patients; Perfusion; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Prevalence; Prevention; Prevention strategy; Preventive treatment; Proliferating; Quality of life; Rattus; Refractory; Research; Research Personnel; Rodent; Safety; Scientist; Skin Cancer; Spinal; Spinal Ganglia; Sprague-Dawley Rats; Structure; Supervision; Technology; Testing; Therapeutic Intervention; Time; Toxic effect; Training; Translating; Treatment Efficacy; Treatment outcome; Tumor-associated macrophages; Universities; Vertebral column; Work; attenuation; cancer cell; cancer pain; cancer therapy; career; chemotherapy; chronic pain patient; chronic painful condition; clinically relevant; control theory; debilitating pain; dorsal column; experimental study; improved; insight; malignant stomach neoplasm; medical schools; meetings; minimally invasive; neuroimmunology; neuronal excitability; neuroregulation; novel; pain behavior; pain inhibition; painful neuropathy; prevent; recruit; side effect; somatosensory; tool; translational study; treatment optimization; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment drugs that often presents as debilitating pain in a stocking-and-glove distribution. One plausible solution is spinal cord stimulation (SCS), a minimally invasive treatment used for refractory neuropathic pain conditions, yet the utility in CIPN pain treatment is unclear. SCS was historically thought to mediate pain inhibition via the gate-control theory, whereby electrical stimulation of the dorsal column activates Aβ afferents, which then inhibit nociceptive afferents (Aδ and C fibers); however, novel waveforms act independent of Aβ activation and a number of non-neuronal mechanisms have been proposed. Accordingly, the long-term goals of this application are to delineate the neuroimmune mechanisms of SCS-induced CIPN pain inhibition. The central hypothesis is that SCS can prevent CIPN pain and enhance chemo-efficacy. This hypothesis will be tested by pursuing three specific aims: 1) Determine the electrical parameters of SCS for prevention of painful CIPN and the underlying neuroimmune mechanisms in the rodent PNS. 2) Determine the vascular and immune mechanisms of SCS-enhanced chemo-efficacy in the tumor microenvironment of human non-small cell lung carcinoma (NSCLC). 3) Elucidate CIPN-associated mechanisms of neuronal hyperexcitability and neuropathic pain in human dorsal root ganglia (DRG). The proposed studies take advantage of state-of-the-art neuroscience tools (calcium imaging, electrophysiology) coupled with cancer-biology and neuroimmunology to delineate how SCS mediates CIPN pain inhibition and enhances paclitaxel efficacy. This work is significant with direct translational relevance since rational SCS parameter selection for CIPN pain treatment and improved chemo-efficacy will lead to improved patient outcomes. Dr. Eellan Sivanesan is a clinician-scientist whose career goals are to become an independently funded cancer pain researcher and a leader in the field of neuromodulation. Dr. Sivanesan will work closely with his mentorship team to develop expertise in cancer- biology, neuroimmunology, and cancer pain. This training will be accomplished primarily through hands-on experiments under supervision of his mentors, as well as structured didactic and non-didactic training, individualized instruction through regular meetings with his mentors, and systematic evaluations. Dr. Sivanesan will be conducting his research within Johns Hopkins University School of Medicine’s Department of Anesthesiology, a thriving academic, clinical, and research environment with exceptional facilities for early stage investigators.

项目摘要 化疗引起的周围神经病变（CIPN）是一种常见的肿瘤剂量限制性副作用 治疗药物，通常表现为在袜子和手套分布的衰弱疼痛。一个貌似有理 解决办法是脊髓刺激（SCS），一种用于难治性神经性疼痛的微创治疗 条件下，但在CIPN疼痛治疗的效用尚不清楚。SCS在历史上被认为介导疼痛 通过门控理论进行抑制，由此背柱的电刺激激活Aβ传入， 然后抑制伤害性传入（Aδ和C纤维）;然而，新的波形不依赖于Aβ 激活和许多非神经元机制。因此，长期目标 描述SCS诱导的CIPN疼痛抑制的神经免疫机制。的 中心假设是SCS可以预防CIPN疼痛并增强化疗功效。这一假设将是 通过追求三个具体目标进行测试：1）确定SCS的电参数，以防止疼痛 CIPN和啮齿动物PNS中的潜在神经免疫机制。2)确定血管和 SCS增强人非小细胞肺癌肿瘤微环境化疗疗效的免疫机制 细胞肺癌（NSCLC）。3)阐明CIPN相关的神经元过度兴奋机制， 人背根神经节（DRG）中的神经病理性疼痛。拟议的研究利用了最先进的 神经科学工具（钙成像，电生理学）结合癌症生物学和神经免疫学， 描述SCS如何介导CIPN疼痛抑制并增强紫杉醇疗效。这项工作意义重大 由于CIPN疼痛治疗的合理SCS参数选择， 化疗功效的改善将改善患者的预后。Eellan Sivanesan博士是一位临床科学家 他的职业目标是成为一名独立资助的癌症疼痛研究人员，并在该领域的领导者。 神经调节Sivanesan博士将与他的导师团队密切合作，发展癌症方面的专业知识- 生物学、神经免疫学和癌症疼痛。这项培训将主要通过实践来完成 在导师的监督下进行实验，以及结构化的教学和非教学培训， 通过与导师的定期会议和系统评估进行个性化指导。博士 Sivanesan将在约翰霍普金斯大学医学院的 麻醉学，一个蓬勃发展的学术，临床和研究环境，具有卓越的设施，为早期 舞台调查员