Investigating the Molecular Mechanism of Hexose-induced Stress in Lens and Retina

描述：糖尿病是一个迅速增加的公共健康问题。控制不好的高血糖会导致糖尿病“晚期并发症”的发生和发展，这些并发症包括白内障和糖尿病视网膜病变，这两种并发症都会导致视力丧失。以前对糖尿病和半乳糖血症动物的研究表明，糖性白内障的形成和糖尿病视网膜病变相关的视网膜血管改变都与渗透压和氧化应激有关，这些应激通过多元醇途径与过量的醛糖还原酶活性有关。过量的醛糖还原酶活性也与信号转导变化、细胞毒信号和细胞凋亡的激活有关。初步研究还表明，醛糖还原酶活性与应激相关基因表达的变化有关。在这项拨款申请中，我们建议阐明(S)晶状体和视网膜中醛糖还原酶活性和己糖诱导的氧化应激与眼部胰岛素样生长因子、转化生长因子和碱性成纤维细胞生长因子水平变化有关的机制(S)，这三种生长因子被认为与白内障形成和糖尿病视网膜病变有关。检测IGF、TGF-β信号通路中MAPK、PI-3K、Smad3的表达水平，以及细胞凋亡因子caspase-3、p53、p38的表达。此外，利用Fox转录因子(IGF1)、Smad3或4(TGF-p)或SAPK/JNK(b-FGF)转录因子将通过微阵列分析确定IGF、转化生长因子-β和b-成纤维细胞生长因子信号通路的主要靶基因。这些研究将在糖尿病和半乳糖喂养的大鼠以及正常和转基因小鼠中进行，在这些小鼠中，视网膜周细胞含有增加的醛糖还原酶水平。通过阐明这种己糖连锁氧化应激的来源和确定醛糖还原酶改变眼部b-FGFIGF-β水平的具体机制(S)，以及它们相关的信号通路和基因表达，可以为白内障和糖尿病视网膜病变的治疗提供新的见解。此外，这些研究应该有助于确定治疗这些糖尿病并发症的新药物靶点。

DESCRIPTION: Diabetes is a rapidly increasing public health problem. Inadequate control of hyperglycemia leads to the onset and progression of the "late complications" of diabetes mellitus which in the eye include cataract and diabetic retinopathy, both of which result in vision loss. Previous studies with diabetic and galactosemic animals have demonstrated that both sugar cataract formation and retinal vascular alterations associated with diabetic retinopathy are linked to osmotic and oxidative stress associated with excess aldose reductase activity through the polyol pathway. Excess aldose reductase activity has also been linked to signal transduction changes, cytotoxic signals and activation of apoptosis. Preliminary studies also indicate that aldose reductase activity is linked to stress-related gene expression changes. In this grant application, we propose to elucidate the mechanism(s) by which aldose reductase activity and hexose-induced oxidative stress in the lens and retina are linked to altered ocular levels of insulin-like growth factor (IGF), transforming growth factor (TGF-beta) and basic fibroblast growth factor (b-FGF), three growth factors observed to be involved in cataract formation and diabetic retinopathy. The levels of MAPK, PI-3K, SMAD3 in the signaling pathways of IGF and TGF-beta and the apoptotic factors, caspase 3, p53, and p38 will be assessed. In addition, the major target genes of IGF, TGF-beta , and b-FGF signaling pathways will be identified using the Fox (IGF1), SMAD3 or 4 (TGF-p), or SAPK/JNK (b-FGF) transcriptional factors with microarray analysis. These studies will be conducted in diabetic and galactose-fed rats and in normal and transgenic mice in which the retinal pericytes contain increased levels of aldose reductase. By clarifying the source of this hexose-linked oxidative stress and identifying the specific mechanism(s) through which aldose reductase alters the ocular levels of b-FGF, IGF and TGF-beta, their associated signaling pathways and gene expression, new insights into the treatment for cataract and diabetic retinopathy can be obtained. Moreover, these studies should help identify new drug targets for the treatment of these diabetic complications.