ELECTROPHYSIOLOGIC MEASURES IN DIABETIC NEUROPATHY

糖尿病多神经病变(DPN)是一个复杂的、往往是潜伏的、多因素的疾病过程。DPN动物模型的价值，包括链脲佐菌素(STZ)诱导的高血糖和基因突变，在很大程度上取决于所使用的替代终点的敏感性和有效性。大多数DPN动物模型都严重依赖于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指标，仅对有限的反应神经元(即大直径、重髓鞘轴突)中的某些神经活动因素敏感。因此，在目前对DPN的许多研究中，人们使用对神经活动的几个关键方面不敏感的主要指标(即最大传导速度)来决定假定的治疗药物以及结构、生化和功能的相关性。这项建议中概述的研究旨在开发和完善一系列新的电生理指标，这些指标可以作为DPN发生和发展的敏感、客观的替代标记物。假设这些更全面的方法的发展将显著扩大我们探索DPN发病机制的能力，并提高我们区分新疗法的机制、时间进程和疗效的能力。我们将评估新的电生理指标，反映中、小直径轴突的活动，记录活动沿远近端梯度的空间分布，并对不应周期和神经疲劳敏感，这反过来又受潜在的跨膜能量利用模式的影响。初步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，以及各种假定治疗药物(即ARL、神经营养因子、超氧阴离子清除剂)的影响。所探索的程序将是非侵入性的、全神经方法，因此将适用于多个实验室和物种，以及可翻译为人类人口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.