Mechanisms of Bortezomib-induced Peripheral Neuropathy

硼替佐米诱发周围神经病变的机制

• 批准号: 8350911
• 负责人: Nathan P Staff
• 金额: $ 14.44万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-04 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8350911
• 关键词: Adverse effects; Axonal Transport; Biological; Bortezomib; Cancer Patient; Cells; Cellular biology; Chronic; Clinical; Consensus Workshop; Data; Development; Development Plans; Disease; Disease model; Distal; Doctor of Medicine; Doctor of Philosophy; Electrophysiology (science); Foundations; Functional disorder; Gated Ion Channel; Goals; Impairment; In Vitro; Incidence; Institution; Investigation; Ion Channel; Kinetics; Knowledge; Link; Malignant Neoplasms; Mediating; Mentors; Mentorship; Microtubules; Mitochondria; Molecular Neurobiology; Neurologist; Neurology; Neuropathy; Neuroprotective Agents; Pain; Patch-Clamp Techniques; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Physicians; Physiological; Prevention; Prevention strategy; Process; Property; Quality of life; Research; Research Personnel; Research Proposals; Risk; Rodent; Scientist; Sodium Channel; Spinal Ganglia; Structure; System; Techniques; Testing; Training; Ubiquitin; Ubiquitination; Velcade; axonal degeneration; base; cancer cell; career; career development; cell killing; cell motility; chemotherapeutic agent; chemotherapy; cost; dosage; ganglion cell; inhibitor/antagonist; multicatalytic endopeptidase complex; neuromuscular; neuronal excitability; neurophysiology; painful neuropathy; patch clamp; prevent; research study; skills; voltage

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side-effect arising in ~400,000 cancer patients yearly and often limits chemotherapy dosage. Pain and other quality of life impairments caused by CIPN are increasing as many forms of cancer become chronic conditions, with an estimated annual cost of ~$2.5 billion dollars (NCI Directors Consensus Workshop, June 2011). It has been assumed that as target-specific therapies were discovered, the off-target effect of peripheral neuropathy would lessen. However, as specific mechanism-based therapies (e.g. proteasome and Jak-2 inhibitors) have been introduced, the incidence of painful, chronic neuropathy has persisted at 30-40% of treated patients. Approaches to limit the impact of CIPN include prevention and symptomatic treatment of neuropathic pain. Preventive strategies are complicated by the risk that protection from CIPN may reduce the primary cancer cell killing effect of a drug. Symptomatic treatments for pain are frequently not successful, reflecting a lack of understanding of the underpinnings of neuropathic pain. In this application, the candidate proposes a comprehensive strategy to understand the biological mechanisms of CIPN caused by a specific chemotherapeutic drug (bortezomib) and the physiologic mechanisms underlying pain caused by the drug. The studies are expected to have broader implications for other diseases of the peripheral nervous system. The candidate is an M.D./Ph.D.-trained neurologist with advanced clinical training in peripheral nerve disorders whose career goal is to perform mechanistic and translational investigations of peripheral nerve disorders and neuropathic pain. Chemotherapy-induced peripheral neuropathy will be used as the model disease system to achieve this goal. The career development plan will be mentored by Dr. Anthony Windebank, a neuromuscular physician-scientist with expertise in CIPN, and Dr. Gianrico Farrugia whose lab focuses on structure-function studies of voltage-gated ion channels. The career development plan combines the strengths of the candidate, the mentors, and the research institution in order to provide an opportunity for the candidate to become a successful independent investigator of peripheral nerve disorders.

描述（由申请人提供）：化学疗法诱导的周围神经病（CIPN）是严重的副作用，每年约有40万例癌症患者，并且通常限制化学疗法剂量。随着许多形式的癌症变为慢性病，疼痛和其他生活质量障碍正在增加，估计每年约为25亿美元的成本（NCI董事共识研讨会，2011年6月）。已经假定，由于发现了目标特异性疗法，周围神经病的脱靶效应将减少。但是，由于已经引入了基于特定机制的疗法（例如蛋白酶体和JAK-2抑制剂），因此疼痛，慢性神经病的发生率持续30-40％。限制CIPN影响的方法包括预防和对神经性疼痛的症状治疗。预防性策略的复杂性使对CIPN的保护可能会降低药物的原发性癌细胞杀死作用。对疼痛的有症状治疗通常无法成功，这反映出对神经性疼痛的基础缺乏了解。在此应用中，候选人提出了一种综合策略，以了解由特定的化学治疗药物（硼替佐米）引起的CIPN的生物学机制以及该药物引起的生理机制。预计该研究对周围神经系统的其他疾病具有更广泛的影响。候选人是一名医学博士/ph.D.训练的神经科医生，对周围神经疾病的高级临床培训，其职业目标是对周围神经疾病和神经性疼痛进行机械和翻译研究。化学疗法引起的周围神经病将被用作实现此目标的模型疾病系统。职业发展计划将由具有CIPN专业知识的神经肌肉医师 - 科学家安东尼·温德班克（Anthony Windebank）博士和Gianrico Farrugia博士的指导，其实验室专注于电压门控离子通道的结构功能研究。职业发展计划结合了候选人，导师和研究机构的优势，以便为候选人提供机会成为周围神经疾病的成功独立研究者的机会。