Mechanism of neuroprotection in chemotherapy induced peripheral neuropathy

化疗所致周围神经病变的神经保护机制

• 批准号: 9027307
• 负责人: Ahmet Hoke
• 金额: $ 35.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027307
• 关键词: Affect; Bortezomib; Calpain; Caspase; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Cisplatin; Client; Clinical Research; Development; Distal; Drug usage; Ethoxyquin; Grant; Heat-Shock Proteins 90; In Vitro; Lead; Life; Link; Mediating; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Mutation; Nervous system structure; Neurologic; Paclitaxel; Pathway interactions; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Play; Proteins; Quality of life; Role; SCA2 protein; Sensory; Treatment Efficacy; Wallerian Degeneration; axonal degeneration; cancer therapy; chemotherapy; chronic neuropathic pain; effective therapy; genetic manipulation; in vivo Model; neuroprotection; neurotoxicity; new therapeutic target; novel; prevent; public health relevance

 DESCRIPTION (provided by applicant): Peripheral neuropathies are major neurological complications of multiple chemotherapy drugs causing significant morbidity affecting quality of life and potentially altering life-saving chemotherapy regimens. Many chemotherapy drugs with diverse mechanisms of actions cause axonal degeneration and the underlying mechanisms that lead to distal axonal degeneration, a common feature of most peripheral neuropathies are poorly understood. Furthermore, currently there are no therapies aimed at preventing, reversing or slowing the progression of peripheral neuropathies that cause chronic neuropathic pain, sensory loss and weakness. In this grant we will approach this problem in two ways. In aim 1, we will examine the molecular mechanisms of distal axonal degeneration induced by paclitaxel as it relates to various pathways that have been linked to Wallerian degeneration. In aim 2, we will examine the molecular mechanisms of a novel neuroprotective compound, ethoxyquin. Recently, we have identified ethoxyquin as a novel neuroprotective compound that interferes with chaperone activity of heat shock protein 90 (hsp90) and prevents distal axonal degeneration induced by a variety of molecular insults, including paclitaxel. Completion of these studies will give us a better understanding of mechanisms of distal axonal degeneration in chemotherapy-induced peripheral neuropathy and help further explore a novel therapeutic target that can be taken to clinical studies in a timely manner.

 描述（由申请人提供）：周围神经病变是多种化疗药物的主要神经系统并发症，可导致显著的发病率，影响生活质量，并可能改变挽救生命的化疗方案。许多具有不同作用机制的化疗药物引起轴突变性和导致远端轴突变性的潜在机制，这是大多数周围神经病变的共同特征，但人们对这些机制的了解甚少。此外，目前没有旨在预防、逆转或减缓引起慢性神经性疼痛、感觉丧失和虚弱的周围神经病的进展的疗法。在这个补助金中，我们将从两个方面来解决这个问题。在目标1中，我们将研究紫杉醇诱导的远端轴突变性的分子机制，因为它涉及与沃勒变性相关的各种途径。在目标2中，我们将研究一种新的神经保护化合物乙氧喹的分子机制。最近，我们已经确定乙氧喹作为一种新的神经保护化合物，干扰伴侣活性的热休克蛋白90（hsp90），并防止远端轴突变性诱导的各种分子损伤，包括紫杉醇。这些研究的完成将使我们更好地了解化疗诱导的周围神经病变中远端轴突变性的机制，并有助于进一步探索新的治疗靶点，可以及时进入临床研究。