Mechanisms of Bortezomib-induced Peripheral Neuropathy

描述(申请人提供)：化疗引起的周围神经病变(CIPN)是一种严重的副作用，每年约有40万癌症患者出现，并经常限制化疗剂量。随着许多形式的癌症变成慢性病，CIPN造成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董事共识研讨会，2011年6月)。人们一直认为，随着靶点特异性治疗方法的发现，周围神经病变的非靶点效应将会减弱。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，疼痛的慢性神经病的发生率一直保持在30%-40%的接受治疗的患者。限制CIPN影响的方法包括神经病理性疼痛的预防和对症治疗。预防策略因CIPN的保护可能会降低药物对原发癌细胞的杀伤作用而变得复杂。疼痛的对症治疗往往不成功，反映出对神经病理性疼痛的基础缺乏了解。在这项申请中，候选人提出了一个全面的策略，以了解特定化疗药物(Bortezomib)引起的CIPN的生物学机制，以及该药物引起疼痛的生理机制。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。应聘者是一名受过医学博士/博士培训的神经科医生，在周围神经疾病方面接受过高级临床培训，其职业目标是对周围神经疾病和神经病理性疼痛进行机械性和转化性研究。化疗诱导的周围神经病变将被用作实现这一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内科医生兼科学家Anthony Windebank博士和Gianrico Farrugia博士指导，他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，以便为候选人提供成为一名成功的周围神经疾病独立研究员的机会。

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.