Mechanisms of Bortezomib-induced Peripheral Neuropathy

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）是每年约40万癌症患者中出现的严重副作用，经常限制化疗剂量。随着许多形式的癌症成为慢性疾病，CIPN引起的疼痛和其他生活质量损害正在增加，估计每年的成本约为25亿美元（NCI主任共识研讨会，2011年6月）。人们一直认为，随着靶向性治疗方法的发现，周围神经病变的脱靶效应将会减轻。然而，随着基于特定机制的治疗（如蛋白酶体和Jak-2抑制剂）的引入，疼痛和慢性神经病变的发生率持续存在于30-40%的治疗患者中。限制CIPN影响的方法包括预防和神经性疼痛的对症治疗。预防策略由于预防CIPN可能降低药物的原发性癌细胞杀伤作用的风险而变得复杂。对疼痛的对症治疗往往不成功，反映了缺乏对神经性疼痛基础的理解。在本申请中，候选人提出了一个全面的策略，以了解由特定化疗药物（硼替佐米）引起的CIPN的生物学机制以及该药物引起的疼痛的生理机制。这些研究有望对周围神经系统的其他疾病产生更广泛的影响。候选人是医学博士。受过外周神经疾病高级临床训练的神经科医生，其职业目标是对外周神经疾病和神经性疼痛进行机械和转化性研究。化疗引起的周围神经病变将作为模型疾病系统来实现这一目标。职业发展计划将由安东尼·温德班克博士和吉安里科·法鲁吉亚博士指导，安东尼博士是一位神经肌肉医生兼科学家，在CIPN方面具有专长，吉安里科·法鲁吉亚博士的实验室专注于电压门控离子通道的结构功能研究。职业发展计划将候选人、导师和研究机构的优势结合起来，为候选人提供成为一名成功的周围神经疾病独立研究者的机会。

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.