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

• 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
• 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

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.

项目摘要/摘要 化学疗法诱导的周围神经病是一种常见的剂量限制毒性，可以降低治疗性 癌症患者的有效性和影响的生活质量。这项研究的总体目标是 确定化学疗法诱导的周围神经病的分子基础，以支持 有针对性的疗法预防和治疗这种毒性。拟议的研究基于反向翻译 药物遗传学方法使用遗传关联发现暗示周围的关键途径 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 化学疗法诱导的神经毒性中的磷酸盐（S1P）信号传导与以前的研究一致 在啮齿动物模型中。本应用程序中提出的研究将扩展这些发现并解决重大 我们对目标细胞中S1P信号传导的毒性，周围感觉神经元的差距。中央 将测试的假设是微管对周围感觉神经元中S1P信号的调节 靶向剂在其神经毒性中起关键作用。人类诱导的多能干细胞得出 所有研究都将采用化学疗法神经毒性（IPS-SNS）的感觉神经元模型。 药理和遗传方法将用于调节S1P信号传导和询问 化学疗法毒性与该信号通路有关。这三个目标是互补的和地址 S1P的离散功能。第一个目标将研究微管靶向剂是否改变鞘脂 感觉神经元中的代谢，并将特定的S1P受体与细胞骨架变化联系起来。研究 在第二个目标中提出的将重点放在S1P受体下游的Rho GTPase信号传导上，并将 建立S1P信号轴，这对于化学疗法诱导的神经突结构的变化至关重要 缩回灯泡的发展。第三个目标将使用scrna-seq和sc-atacseq阐明是否阐明 紫杉醇诱导的IPS-SNS基因表达变化涉及S1P对染色质可及性的影响。这 fingolimod的能力，一种靶向S1P受体信号的多发性硬化症疗法，目前正在 测试了预防和治疗紫杉醇诱导的周围神经病，以防止 将检查化学疗法引起的神经毒性。总的来说，这些研究将揭示分子 响应微管的感觉神经元中轴突变性的基础机制 靶向剂并阐明了用芬洛莫德神经保护的新机制。