Identification of susceptibility to chemotherapy induced peripheral neuropathy using patient stem cell derived sensory neurons

使用患者干细胞来源的感觉神经元鉴定对化疗引起的周围神经病变的易感性

基本信息

批准号：
9385404
负责人：
CLIFFORD J WOOLF
金额：
$ 8.85万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385404
关键词：
Adverse effects Affect Afferent Neurons Age Antineoplastic Agents Biological Assay Cancer Survivor Cardiac Myocytes Cardiotoxicity Cells Chemotherapy-induced peripheral neuropathy Chicago Clinical Development Diagnostic Dose Doxorubicin Drug Modelings Drug toxicity Exposure to Functional disorder Funding Future Gender Generic Drugs Genetic Genetic study Human In Vitro Incidence Individual Length Limb structure Measures Mitochondria Modeling Muscle Cramp Muscle Weakness Neurites Neurons Neuropathy Numbness Outcome Study Paclitaxel Patient risk Patients Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Phenotype Physicians Pilot Projects Predisposition Prevention Proteasome Inhibitor Proxy Regimen Relative Risks Risk Risk Factors Sample Size Screening Result Specificity Stem cells Symptoms Testing Toxic effect Treatment Protocols United States Universities Vinca Alkaloids base chemotherapeutic agent chemotherapy cohort experience in vitro Model induced pluripotent stem cell mRNA Differential Displays neuronal excitability neurotoxicity novel therapeutics painful neuropathy response screening taxane therapeutic target

项目摘要

Project Summary/Abstract Identification of susceptibility to chemotherapy induced peripheral neuropathy using patient stem cell derived sensory neurons Current understanding of the mechanisms responsible for chemotherapy induced peripheral neuropathy (CIPN) is extremely limited and more importantly, there is no way of identifying who is at risk. In this proposal, we will test the utility of an in-vitro model of CIPN using human neurons generated from patient-derived stem cells for the study of CIPN risk. Sensory neurons, the neurons most commonly affected in CIPN, will be generated from iPSC lines generated from patients treated with the chemotherapeutic paclitaxel who did, or did not, develop CIPN. The susceptibility of these neurons to paclitaxel-induced neurotoxicity will be measured to determine whether neurons from individuals with CIPN are more vulnerable to chemotherapeutic neurotoxicity than those from their age, gender and dose matched controls who did not develop CIPN. The sensory neurons will also be exposed to other classes of chemotherapeutic agents, which also cause peripheral neuropathy despite distinct antineoplastic mechanisms, to determine whether sensory neuron susceptibility to chemotherapy-induced toxicity is generic or specific to certain classes of drug. These findings could contribute to identifying patients at risk for CIPN prior to their treatment and understanding the factors which contribute to CIPN susceptibility.

项目摘要/摘要使用衍生的患者干细胞鉴定化学疗法诱导的外周神经病的易感性感觉神经元当前对负责化学疗法诱导周围神经病的机制的理解（CIPN）非常有限，更重要的是，无法确定谁处于危险之中。在此提案中，我们将使用由患者来源的茎产生的人神经元测试CIPN的体外模型的实用性用于研究CIPN风险的细胞。感觉神经元，最常见于CIPN的神经元将是由由化学治疗性紫杉醇治疗的患者产生的IPSC线产生的不，开发CIPN。这些神经元对紫杉醇诱导的神经毒性的敏感性将被测量为确定来自CIPN个体的神经元是否更容易受到化学治疗性神经毒性的影响比他们年龄的人，性别和剂量匹配没有开发CIPN的对照。感觉神经元还将暴露于其他类别的化学治疗剂，这也会引起周围神经病尽管有不同的抗塑性机制，但要确定感觉神经元的敏感性是否化学疗法诱导的毒性是某些类别的药物的通用或特异性的。这些发现可能会做出贡献在治疗之前识别有CIPN风险的患者，并了解导致的因素 CIPN敏感性。