Axonal transport and chemotherapy induced peripheral neuropathy

轴突运输和化疗引起的周围神经病变

基本信息

批准号：
10649524
负责人：
ROSALIND A. SEGAL
金额：
$ 57.85万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649524
关键词：
Address Afferent Neurons Aftercare Alzheimer&apos s Disease Antimitotic Agents Antineoplastic Agents Axon Axonal Transport Binding Calpain Cancer Patient Cancer Survivor Cells Chemotherapy-induced peripheral neuropathy Complication Cyclic ADP-Ribose Cytoplasmic Granules Data Defect Disease Exhibits Family member Foundations Funding Gases Genetic study Goals Grant Human ITPR1 gene Immunocompetent Induced pluripotent stem cell derived neurons Intervention Link Malignant Neoplasms Mediating Messenger RNA Microtubule Stabilization Microtubules Modeling Motor Neurons Mus Nerve Nerve Degeneration Nervous System Nervous System Physiology Neurologic Neurons Neuropathy Numbness Paclitaxel Pain Pathologic Pathway interactions Patients Peptide Hydrolases Persons Pharmaceutical Preparations Predisposition Presynaptic Terminals Principal Investigator Process Production Proteins Quality of life RNA Transport Resistance Resources Rodent Role Sensory Symptoms Testing Therapeutic Toxic effect Translations Vinca Alkaloids Withholding Treatment Writing antagonist anterograde transport axonal degeneration axonopathy cancer therapy chemotherapy effective therapy experience hereditary neuropathy improved induced pluripotent stem cell inhibitor innovation insight malignant breast neoplasm mimetics mouse model neoplastic cell nerve supply novel strategies novel therapeutic intervention novel therapeutics optimal treatments prevent prognostic indicator retrograde transport sulfated glycoprotein 2 taxane therapeutic target treatment response tumor tumor growth

项目摘要

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating sequela for many cancer patients. For some patients this complication prevents optimal therapy and so jeopardizes the chance for a cure, while many patients develop permanent, untreatable pain and severe sensory deficits that seriously compromise quality of life for cancer patients and survivors. The mechanisms that cause axon degeneration and sensory symptoms in CIPN are just beginning to be defined, and it is not yet clear whether the mechanisms that underlie CIPN can be biologically resolved from anti-neoplastic efficacy of chemotherapy. Against this backdrop, our previous studies under this grant have demonstrated a central role for increased axonal Ca+2 and activation of Ca+2-dependent calpain proteases in CIPN. Building on these findings we will identify the processes linking together 1) the direct effects of paclitaxel or other chemotherapies on microtubules, 2) activation of molecules implicated in axon destruction, plus the loss of compounds that promote axon survival and 3) opening of Ca+2 channels located within the long axons. Our studies make use of rodent sensory neurons in compartmented cultures, immunocompetent mice with paclitaxel-sensitive breast cancer, and new human iPSC-derived sensory neuron cultures prepared from patients with severe CIPN or from patients resistant to CIPN. Using these innovative approaches we will identify therapeutic targets for treating CIPN without compromising the anti-neoplastic efficacy of paclitaxel and we will develop novel therapeutic compounds. Since the process of axon degeneration in CIPN is similar to that seen in diseases including hereditary neuropathy, ALS, and Alzheimer’s disease, our insights and therapeutic approaches will advance treatment for many additional debilitating diseases.

抽象的化疗引起的周围神经病变 (CIPN) 是许多癌症的一种痛苦且令人衰弱的后遗症对于一些患者来说，这种并发症阻碍了最佳治疗，从而危及了获得治疗的机会。治愈，而许多患者会出现永久性的、无法治愈的疼痛和严重的感觉缺陷，严重影响损害癌症患者和幸存者的生活质量导致轴突变性的机制。 CIPN 中的感觉症状和感觉症状刚刚开始被定义，目前尚不清楚是否 CIPN 背后的机制可以从化学疗法的抗肿瘤功效中得到生物学解决。在此背景下，我们之前在这笔赠款下的研究表明，增加 CIPN 中轴突 Ca+2 和 Ca+2 依赖性钙蛋白酶的激活基于这些发现，我们将。确定连接在一起的过程 1) 紫杉醇或其他化疗对患者的直接影响微管，2) 参与轴突破坏的分子的激活，以及导致轴突破坏的化合物的损失促进轴突存活和 3) 打开位于长轴突内的 Ca+2 通道。隔室培养物中啮齿动物感觉神经元的变化，具有紫杉醇敏感乳腺的免疫活性小鼠癌症，以及从患有严重 CIPN 或严重 CIPN 的患者中制备的新的人类 iPSC 衍生的感觉神经元培养物利用这些创新方法，我们将确定针对 CIPN 耐药的患者的治疗靶点。在不影响紫杉醇抗肿瘤功效的情况下治疗 CIPN，我们将开发新的由于 CIPN 中的轴突变性过程与疾病中所见的过程相似。包括遗传性神经病、ALS 和阿尔茨海默病，我们的见解和治疗方法将治疗许多其他使人衰弱的疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy.

DOI：
10.3389/fnins.2017.00481
发表时间：
2017
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Fukuda Y;Li Y;Segal RA
通讯作者：
Segal RA

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.

DOI：
10.1159/000512976
发表时间：
2020
期刊：
Developmental neuroscience
影响因子：
2.9
作者：
Merk DJ;Zhou P;Cohen SM;Pazyra-Murphy MF;Hwang GH;Rehm KJ;Alfaro J;Reid CM;Zhao X;Park E;Xu PX;Chan JA;Eck MJ;Nazemi KJ;Harwell CC;Segal RA
通讯作者：
Segal RA