Mechanisms of Bortezomib-induced Peripheral Neuropathy

描述（由申请人提供）：化疗诱导的周围神经病变（CIPN）是一种严重的副作用，每年约有40万例癌症患者出现，通常会限制化疗剂量。随着许多形式的癌症变成慢性病症，由CIPN引起的疼痛和其他生活质量损害正在增加，估计每年花费约25亿美元（NCI董事共识研讨会，2011年6月）。据推测，随着靶向特异性治疗的发现，周围神经病变的脱靶效应将减少。然而，随着基于特定机制的治疗（例如蛋白酶体和Jak-2抑制剂）的引入，疼痛性慢性神经病变的发生率在30-40%的治疗患者中持续存在。限制CIPN影响的方法包括预防和对症治疗神经性疼痛。预防策略因CIPN保护可能降低药物的原发性癌细胞杀伤作用的风险而复杂化。疼痛的对症治疗通常不成功，反映了对神经性疼痛基础的缺乏了解。在这项申请中，候选人提出了一个全面的策略，以了解由特定的化疗药物（硼替佐米）引起的CIPN的生物学机制和由药物引起的疼痛的生理机制。这些研究预计将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/博士学位-接受过周围神经疾病高级临床培训的神经科医生，其职业目标是对周围神经疾病和神经性疼痛进行机械和转化研究。化疗诱导的周围神经病变将被用作模型疾病系统，以实现这一目标。职业发展计划将由Anthony Windebank博士和Gianrico Farrugia博士指导，Anthony Windebank博士是一位在CIPN方面具有专业知识的神经肌肉医生科学家，Gianrico Farrugia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。

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.