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.

周围神经病是与糖尿病。然而，尽管它的流行和衰弱后果，糖尿病神经病的发病机理仍然是一个谜。虽然高血糖已被确定为基本代谢干扰，早期代谢事件之间的关系是特征的通过电生理异常和随后的结构变化神经仍然不清楚。先前的工作表明高血糖引起的，夸张的多元元通道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，多元元通道通量已显示与退化性schwann细胞变化，轴突减少，收缩变化和肌化纤维变性时，当键酶的键途径，醛糖还原酶被抑制。如何抑制醛还原酶是雪旺细胞和肌纤维中存在的一种酶，可以恢复除非夸张的多元型途径活性破坏Schwann细胞和/或骨骼肌代谢的其他方面这会影响轴突结构和功能的维护。纤毛神经营养因子（CNTF），一种雪旺细胞衍生的神经营养因子与神经丝合成有关，在实验中降低糖尿病，可能代表能够影响维护的事实轴突结构和功能。神经的合成和释放生长因子（NGF）和脑衍生的神经营养因子（BDNF），两个神经营养蛋白通常位于骨骼肌，但神经损伤后在增殖的雪旺细胞中也可能被多元醇破坏积累，因此对轴突的维持产生不利影响实验性糖尿病的结构和功能以及再生。该提案中概述的研究的总体目标是检查高血糖诱导的夸张的多元元路径的可能性活动阻碍了神经营养因素的产生破坏轴突功能和结构的维护和障碍应对伤害的能力。这些实验将与实验性糖尿病的两个鲜明的啮齿动物模型：半乳糖中毒和链蛋白酶糖尿病。具体目标是组织分为三个类别：1）高血糖对神经营养的生物活性，蛋白质，mRNA和逆行转运因素； 2）外源性神经营养因子治疗对电生理，慢速轴突运输和结构异常可能是由多元元积累引起的； 3）实验性糖尿病在schwann细胞衍生的表达挤压损伤后的神经营养因素和外源性的影响关于再生的发生率和质量的治疗。因此，这个研究建议将整合生理，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素缺陷引起的结构异常在实验性糖尿病中。