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

基本信息

批准号：
9765421
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-08-31
项目状态：
已结题

项目摘要

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（由适用提供）：周围神经病是多种化疗药物的主要神经系统并发症，导致明显的发病率影响生活质量并可能改变挽救生命的化学疗法方案。许多具有不同作用机制的化学疗法药物会导致轴突变性和导致轴突变性的潜在机制，大多数周围神经病的共同特征是不足的。此外，目前尚无旨在防止，逆转或减慢周围神经病的进展，导致慢性神经性疼痛，感觉丧失和无力。在AIM 1中，我们将通过两种方式解决此问题。在AIM 1中，我们将检查紫杉醇与沃勒式变性有关的各种途径，紫杉醇引起的远端轴突变性的分子机制。在AIM 2中，我们将检查一种新型神经保护化合物乙氧基喹的分子机制。最近，我们已经确定乙氧基喹是一种新型的神经保护化合物，它干扰了热休克蛋白90（HSP90）的伴侣活性，并防止由包括紫杉醇在内的多种分子感染引起的远端轴突变性。这些研究的完成将使我们更好地理解化学疗法诱导的周围神经病中轴突变性的机制，并有助于进一步探索一个新的治疗靶点，可以及时将其用于临床研究。