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: 10437909
• 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/10437909
• 关键词: 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 Research; 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; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; 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; Quality of life; Rattus; Refractory; Research; Research Personnel; Rodent; Safety; Scientist; Skin Cancer; Spinal; Spinal Ganglia; Sprague-Dawley Rats; Structure; Supervision; Testing; Therapeutic Intervention; Time; Toxic effect; Training; Translating; Treatment outcome; Tumor-associated macrophages; Universities; 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; macrophage; 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.

项目概要 化疗引起的周围神经病变（CIPN）是癌症常见的剂量限制性副作用 一种看似合理的治疗方法是，通常将药物表现为使人衰弱的疼痛，并在袜子和手套中分发。 解决方案是脊髓刺激 (SCS)，这是一种用于治疗难治性神经病理性疼痛的微创治疗方法 但 SCS 在 CIPN 疼痛治疗中的效用尚不清楚，历史上人们认为 SCS 可以调节疼痛。 通过门控理论进行抑制，即电刺激背柱激活 Aβ 传入神经， 然后抑制伤害性传入神经（Aδ 和 C 纤维）；然而，新的波形独立于 Aβ 起作用； 因此，已经提出了长期目标。 本申请的目的是描述 SCS 诱导的 CIPN 疼痛抑制的神经免疫机制。 中心假设是 SCS 可以预防 CIPN 疼痛并增强化疗疗效。 通过追求三个具体目标进行测试：1）确定 SCS 的电参数以预防疼痛 CIPN 和啮齿动物 PNS 的潜在神经免疫机制 2) 确定血管和神经免疫机制。 SCS增强人类非小细胞肿瘤微环境化疗功效的免疫机制 细胞肺癌 (NSCLC) 3) 阐明 CIPN 相关的神经元过度兴奋和 人类背根神经节（DRG）的神经性疼痛所提出的研究利用了最先进的技术。 神经科学工具（钙成像、电生理学）与癌症生物学和神经免疫学相结合， 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。 具有直接的转化相关性，因为 CIPN 疼痛治疗的合理 SCS 参数选择和 Eellan Sivanesan 博士是一位临床医生科学家，提高化疗效果将改善患者的治疗效果。 其职业目标是成为一名独立资助的癌症疼痛研究员和该领域的领导者 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。 该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。 Sivanesan 将在约翰霍普金斯大学医学院的系内进行他的研究 麻醉学是一个蓬勃发展的学术、临床和研究环境，为早期麻醉学提供了卓越的设施 阶段调查员。