Sphingolipid Signaling and Chemotherapy-Induced Peripheral Neurotoxicity

鞘脂信号传导和化疗引起的周围神经毒性

基本信息

批准号：
10230429
负责人：
Deanna L Kroetz
金额：
$ 57.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10230429
关键词：
ATAC-seq Address Affect Afferent Neurons Cancer Patient Cells Chemotherapy-Oncologic Procedure Chemotherapy-induced peripheral neuropathy Chromatin Clinical Clinical Trials Coupled Critical Pathways Data Development Dose-Limiting Drug usage Event GTP-Binding Proteins Gene Expression Gene Expression Regulation Genes Genetic Polymorphism Genetic Transcription Genomic approach Goals High Prevalence Histone Deacetylase Histone Deacetylase Inhibitor Human Knowledge Lead Link Malignant Neoplasms Measures Mediating Metabolism Microtubules Modeling Molecular Molecular Conformation Morphology Multiple Sclerosis Neurites Neurons Paclitaxel Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmacogenetics Pharmacology Pharmacotherapy Play Prevention Quality of life Receptor Signaling Regulation Research Risk Rodent Rodent Model Role Serious Adverse Event Signal Pathway Signal Transduction Sphingolipids Sphingosine-1-Phosphate Receptor Structure Testing Therapeutic Time Toxic effect Toxicity due to chemotherapy Translating Validation Work axonal degeneration base cancer therapy chemotherapy chromatin modification experimental study genetic approach genetic association improved induced pluripotent stem cell inorganic phosphate mortality multiple sclerosis treatment neuroprotection neurotoxic neurotoxicity novel patient safety prevent receptor-mediated signaling response rho GTP-Binding Proteins single-cell RNA sequencing sphingosine 1-phosphate survival outcome targeted agent targeted treatment therapeutic effectiveness translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Chemotherapy induced peripheral neuropathy is a common dose-limiting toxicity that can reduce therapeutic effectiveness and impact quality of life for cancer patients. The overarching goal of this research is to determine the molecular basis of chemotherapy-induced peripheral neuropathy to support the development of targeted therapies to prevent and treat this toxicity. The proposed studies are based on a reverse translational pharmacogenetic approach that uses genetic association findings to implicate critical pathways in peripheral neuropathy. Recent genetic association and functional validation findings support a role for sphingosine-1- phosphate (S1P) signaling in chemotherapy-induced neurotoxicity, which are consistent with previous studies in rodent models. The studies proposed in this application will extend these findings and address a significant gap in our knowledge of S1P signaling in target cells for toxicity, peripheral sensory neurons. The central hypothesis that will be tested is that modulation of S1P signaling in peripheral sensory neurons by microtubule targeting agents plays a critical role in their neurotoxicity. A human induced pluripotent stem cell derived sensory neuron model of chemotherapy neurotoxicity (iPS-SNs) will be employed for all studies. Pharmacological and genetic approaches will be used to modulate S1P signaling and interrogate chemotherapy toxicity linked to this signaling pathway. The three aims are complementary and address discrete functions of S1P. The first aim will investigate whether microtubule targeting agents alter sphingolipid metabolism in sensory neurons and will link specific S1P receptors to cytoskeletal changes. The studies proposed in the second aim will focus on Rho GTPase signaling downstream of S1P receptors and will establish the S1P signaling axis that is critical for chemotherapy-induced changes in neurite structure and the development of retraction bulbs. The third aim will use scRNA-seq and sc-ATACseq to elucidate whether paclitaxel-induced changes in gene expression in iPS-SNs involve S1P effects on chromatin accessibility. The ability of fingolimod, a multiple sclerosis therapy that targets S1P receptor signaling and is currently being tested for prevention and treatment of paclitaxel-induced peripheral neuropathy, to protect against chemotherapy-induced neurotoxicity will be examined. Collectively, these studies will reveal molecular mechanisms underlying the axon degeneration that occurs in sensory neurons in response to microtubule targeting agents and elucidate novel mechanisms for neuroprotection with fingolimod.

项目概要/摘要化疗引起的周围神经病变是一种常见的剂量限制性毒性，可降低治疗效果有效性和对癌症患者生活质量的影响。这项研究的总体目标是确定化疗引起的周围神经病变的分子基础，以支持发展预防和治疗这种毒性的靶向疗法。拟议的研究基于逆翻译药物遗传学方法，利用遗传关联发现来暗示外周血中的关键通路神经病。最近的遗传关联和功能验证结果支持鞘氨醇-1-的作用磷酸盐（S1P）信号在化疗引起的神经毒性中的作用，这与之前的研究一致在啮齿动物模型中。本申请中提出的研究将扩展这些发现并解决一个重要问题我们对靶细胞中毒性、外周感觉神经元的 S1P 信号传导的了解存在差距。中央将要检验的假设是微管对周围感觉神经元中 S1P 信号的调节靶向药物在其神经毒性中起着关键作用。源自人类的诱导多能干细胞所有研究都将采用化疗神经毒性的感觉神经元模型（iPS-SN）。药理学和遗传学方法将用于调节 S1P 信号传导并询问化疗毒性与该信号通路有关。这三个目标是互补的并解决 S1P 的离散函数。第一个目标是研究微管靶向剂是否改变鞘脂感觉神经元的代谢，并将特定的 S1P 受体与细胞骨架的变化联系起来。研究第二个目标中提出的重点是 S1P 受体下游的 Rho GTPase 信号传导，并将建立 S1P 信号轴，这对于化疗引起的神经突结构和神经突结构的变化至关重要开发回缩灯泡。第三个目标将使用 scRNA-seq 和 sc-ATACseq 来阐明是否紫杉醇诱导的 iPS-SN 基因表达变化涉及 S1P 对染色质可及性的影响。这芬戈莫德是一种针对 S1P 受体信号传导的多发性硬化症疗法，目前正在研究中测试用于预防和治疗紫杉醇引起的周围神经病变，以防止将检查化疗引起的神经毒性。总的来说，这些研究将揭示分子感觉神经元响应微管而发生轴突变性的机制靶向药物并阐明芬戈莫德神经保护的新机制。