Mechanism of neuroprotection in chemotherapy induced peripheral neuropathy

 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，导致显着的发病率，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会导致轴突变性，而导致远端轴突变性（大多数周围神经病的一个共同特征）的潜在机制尚不清楚。此外，目前还没有旨在预防、逆转或减缓导致慢性神经性疼痛、感觉丧失和无力的周围神经病进展的疗法。在这笔赠款中，我们将通过两种方式解决这个问题。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，因为它与与沃勒变性相关的各种途径有关。在目标 2 中，我们将研究一种新型神经保护化合物乙氧基喹的分子机制。最近，我们发现乙氧基喹啉是一种新型神经保护化合物，可干扰热休克蛋白 90 (hsp90) 的伴侣活性，并防止由包括紫杉醇在内的多种分子损伤引起的远端轴突变性。这些研究的完成将使我们更好地了解化疗引起的周围神经病变远端轴突变性的机制，并有助于进一步探索可及时进入临床研究的新治疗靶点。

 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.