ELECTROPHYSIOLOGIC MEASURES IN DIABETIC NEUROPATHY

糖尿病性多发性神经病（DPN）是一种复杂的，往往是阴险和多因素的疾病过程。 DPN动物模型的价值，包括链脲佐菌素（STZ）和基因突变诱导的高血糖症，在很大程度上取决于所用替代终点的敏感性和有效性。 大多数DPN动物模型严重依赖（如果不是唯一的话）最大神经传导速度的变化作为神经功能的指标。“虽然客观可靠，但最大神经传导速度是一种高度选择性的测量方法，仅对有限的响应神经元子集（即大直径，重髓鞘轴突）中的神经活动的某些元素敏感。 因此，在目前的许多DPN研究中，正在使用对神经活动的几个关键方面不敏感的主要测量（即最大传导速度）来决定推定的治疗剂以及结构、生物化学和功能的相关性。 本提案中概述的研究旨在开发和完善一组新的电生理测量方法，这些方法可作为DPN发作和进展的敏感、客观、替代标志物。 据推测，这些更全面的措施的发展将显着扩大我们的能力，探索DPN的发病机制，以及提高我们的能力，区分机制，时间过程和新的治疗方法的疗效。 我们将评估新的电生理措施，反映活动中，小直径轴突，注册的空间分布活动沿着远端到近端的梯度和敏感的不应期和神经疲劳，这反过来又影响了跨膜能量利用的基本模式。 最初的研究将检查新措施的技术细节和可靠性;随后的研究将检查这些措施在STZ诱导的DPN模型中的价值以及各种类型的推定治疗剂（即ARIs，神经营养因子，超氧化物清除剂）的影响。 探索的程序将是非侵入性的，全神经的方法，因此将适用于多个实验室和物种，以及在人群研究和临床试验中的电生理测量。

Diabetic polyneuropathy (DPN) is a complex, often insidious and multifactorial disease process. The value of animal models of DPN, including hyperglycemia induced by streptozocin (STZ) and genetic mutations, is largely determined by the sensitivity and validity of the surrogate endpoints utilized. Most animal models of DPN have relied heavily, if not exclusively, on changes in maximal nerve conduction velocity as an index of nerve "function." Although objective and reliable, maximal nerve conduction velocity is a highly selective measure, sensitive to only some elements of neural activity in only a limited subset of responding neurons (i.e. large diameter, heavily myelinated axons). Thus, in many current studies of DPN, decisions are being made about putative therapeutic agents and about correlations of structure, biochemistry and function using a principal measure (i.e. maximal conduction velocity) that is insensitive to several key aspects of neural activity. The studies outlined in this proposal are intended to develop and refine a new battery of electrophysiologic measures, which could serve as sensitive, objective, surrogate markers for the onset and progression of DPN. It is hypothesized that the development of these more comprehensive measures would significantly expand our ability to explore the pathogenesis of DPN, as well as improve our ability to distinguish the mechanism, time course and efficacy of new therapies. We will evaluate new electrophysiologic measures that reflect activity in medium and small diameter axons, register the spatial distributions of activity along distal-to-proximal gradients and are sensitive to refractory cycles and neural fatigue, which are in turn influenced by the underlying pattern of transmembrane energy utilization. Initial studies will examine the technical details and reliability of the new measures; later studies will examine the value of these measures in an STZ-induced model of DPN and the impact of various classes of putative therapeutic agents (i.e. ARls, neurotrophic factors, superoxide scavengers). The procedures explored will be non-invasive, whole nerve methods and will therefore be applicable to multiple laboratories and species, as well as translatable to electrophysiologic measures in human population studies and clinical trials.