POLYOL PATHWAY AND NEUROTROPHIC FACTORS IN DIABETES

糖尿病中的多元醇途径和神经营养因子

基本信息

批准号：
2460566
负责人：
ANDREW P MIZISIN
金额：
$ 22.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2460566
关键词：
Schwann cells axon diabetes mellitus diabetic neuropathy electrophysiology hyperglycemia laboratory rat medical complication messenger RNA nervous system regeneration neuronal transport neurotrophic factors striated muscles

项目摘要

Peripheral neuropathy is the most common complication associated with diabetes mellitus. Yet, in spite of its prevalence and debilitating consequences, the pathogenesis of diabetic neuropathy remains an enigma. While hyperglycemia has been identified as the fundamental metabolic disturbance, the relationship between early metabolic events characterized by electrophysiologic abnormalities and subsequent structural changes of nerve remains unclear. Previous work has shown that hyperglycemia-induced, exaggerated polyol-pathway flux underlies a number of the biochemical and functional disorders in experimental diabetes. More recently, in nerve and muscle, polyol-pathway flux has been shown to be associated with degenerative Schwann cell changes, axonal dwindling, contractile changes and myofiber degeneration that are prevented when the key enzyme of the pathway, aldose reductase, is inhibited. How inhibition of aldose reductase, an enzyme present in Schwann cells and myofibers, can restore axonal caliber is puzzling unless exaggerated polyol pathway activity disrupts other aspects of Schwann cell and/or skeletal muscle metabolism that influence the maintenance of axonal structure and function. Ciliary neurotrophic factor (CNTF), a Schwann cell-derived neurotrophic factor implicated in neurofilament synthesis, is decreased in experimental diabetes and may represent a facto capable of influencing the maintenance of axonal structure and function. The synthesis and release of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two neurotrophins normally localized to skeletal muscle but after nerve injury also found in proliferating Schwann cells, may also be disrupted by polyol accumulation and thus have an adverse impact on the maintenance of axonal structure and function, as well as regeneration in experimental diabetes. The overall goal of the research outlined in this proposal is to examine the possibility that hyperglycemia-induced, exaggerated polyol-pathway activity hinders the production of neurotrophic factors, thereby disrupting the maintenance of axonal function and structure and impairing the ability to respond to injury. These experiments will be conducted with two well characterized rodent models of experimental diabetes: galactose intoxication and streptozotocin diabetes. The specific objectives are organized into three broad categories: 1) the impact of hyperglycemia on the bioactivity, protein, mRNA and retrograde transport of neurotrophic factors; 2) the impact of exogenous neurotrophic factor treatment on electrophysiologic, slow axonal transport and structural abnormalities likely to result from polyol accumulation; and 3) the impact of experimental diabetes on the expression of Schwann cell-derived neurotrophic factors after crush injury and the effect of exogenous treatment on the incidence and quality of regeneration. Thus, this research proposal will integrate physiologic, biochemical, morphologic and molecular biologic techniques to determine and study the functional and structural abnormalities resulting from deficits of neurotrophic factors in experimental diabetes.

周围神经病变是最常见的并发症糖尿病。然而，尽管其普遍存在且令人衰弱然而，糖尿病神经病变的发病机制仍然是一个谜。虽然高血糖已被确定为基本代谢紊乱，早期代谢事件之间的关系通过电生理异常和随后的结构变化神经仍不清楚。先前的工作表明，高血糖引起的，夸大的多元醇途径通量是许多生化和实验性糖尿病的功能障碍。最近，在神经和肌肉，多元醇途径通量已被证明与退行性雪旺细胞变化、轴突萎缩、收缩变化和肌纤维变性，当肌纤维的关键酶被阻止时醛糖还原酶途径受到抑制。如何抑制醛糖还原酶是雪旺细胞和肌纤维中存在的一种酶，可以恢复除非夸大多元醇途径活性，否则轴突口径令人费解破坏雪旺细胞和/或骨骼肌代谢的其他方面影响轴突结构和功能的维持。睫状体神经营养因子（CNTF），一种雪旺细胞源性神经营养因子与神经丝合成有关，在实验中减少糖尿病，并可能代表一个能够影响维持的因素轴突的结构和功能。神经的合成与释放生长因子（NGF）和脑源性神经营养因子（BDNF），两种神经营养素通常定位于骨骼肌，但在神经损伤后也存在于增殖的雪旺细胞中，也可能被多元醇破坏积累，从而对轴突的维持产生不利影响结构和功能，以及实验性糖尿病的再生。本提案中概述的研究的总体目标是检查高血糖引起的、夸大的多元醇途径的可能性活性阻碍神经营养因子的产生，从而破坏轴突功能和结构的维持并损害对伤害做出反应的能力。这些实验将进行两种特征明确的实验性糖尿病啮齿动物模型：半乳糖中毒和链脲佐菌素糖尿病。具体目标是分为三大类：1）高血糖对身体的影响神经营养物质的生物活性、蛋白质、mRNA 和逆行转运因素； 2）外源性神经营养因子治疗对神经营养因子的影响电生理学、缓慢轴突运输和结构异常可能是多元醇积累造成的； 3) 的影响实验性糖尿病对雪旺细胞源表达的影响挤压伤后神经营养因子及外源性因素的影响治疗对再生发生率和质量的影响。因此，这个研究计划将整合生理、生化、形态学和分子生物学技术来确定和研究功能和神经营养因子缺乏导致的结构异常在实验性糖尿病中。