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

研究己糖引起晶状体和视网膜应力的分子机制

• 批准号: 7635754
• 负责人: PETER F KADOR
• 金额: $ 32.12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635754
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aldehyde Reductase; Alleles; Animal Feed; Animals; Apoptosis; Apoptotic; Applications Grants; Binding; Biochemistry; Blindness; Blood Vessels; Blood capillaries; Boxing; Canis familiaris; Cataract; Cell Line; Cell Nucleus; Cell physiology; Cells; Clinical; Complex; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Retinopathy; Drug Delivery Systems; Epithelial Cells; Event; Eye; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Foxes; Galactose; Gene Expression; Gene Targeting; Genes; Glucose; Green Fluorescent Proteins; Growth Factor; Hexoses; Human; Hyperglycemia; IGF1 gene; In Vitro; Induction of Apoptosis; Insulin; Insulin-Like Growth Factor Receptor; Knockout Mice; L-Iditol 2-Dehydrogenase; Lead; Link; MADH3 gene; MAP Kinase Gene; MAPK14 gene; Maintenance; Measures; Microarray Analysis; Molecular; Molecular Biology; N-terminal; Nucleotides; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pericytes; Pharmacology; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Production; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Publishing; RNA; Rattus; Reporting; Research Personnel; Resistance; Retina; Retinal; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Small Interfering RNA; Somatomedins; Source; Stream; Stress; Sugar Alcohols; TP53 gene; Tissues; Toxic effect; Transcription Coactivator; Transducers; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Vascular Endothelial Growth Factors; Vitreous humor; base; capillary; caspase-3; cell growth; cytotoxic; design; diabetic; feeding; glycation; in vivo; inhibitor/antagonist; insight; interest; lens; mitogen-activated protein kinase p38; novel; oxidation; polyol; prevent; programs; receptor; stress activated protein kinase; stress tolerance; stress-activated protein kinase 1; sugar; transcription factor

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.

糖尿病是一个快速增长的公共卫生问题。对高血糖控制不足会导致糖尿病“晚期并发症”的发生和发展，包括白内障和糖尿病性视网膜病变，两者都会导致视力丧失。先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与糖尿病视网膜病变相关的视网膜血管改变都与渗透和氧化应激有关，通过多元醇途径与醛糖还原酶活性过剩有关。过量醛糖还原酶活性也与信号转导改变、细胞毒性信号和细胞凋亡激活有关。初步研究还表明醛糖还原酶活性与应激相关的基因表达变化有关。在这项资助申请中，我们建议阐明晶状体和视网膜中醛糖还原酶活性和自糖诱导的氧化应激与胰岛素样生长因子（IGF）、转化生长因子（tgf - β）和碱性成纤维细胞生长因子（b-FGF）眼部水平改变相关的机制，这三种生长因子被观察到参与白内障形成和糖尿病视网膜病变。评估IGF和tgf - β信号通路中MAPK、PI-3K、SMAD3的水平，以及凋亡因子、caspase 3、p53和p38的水平。此外，IGF、tgf - β和b-FGF信号通路的主要靶基因将通过微阵列分析使用Fox （IGF1）、SMAD3或4 （TGF-p）或SAPK/JNK （b-FGF）转录因子进行鉴定。这些研究将在糖尿病和半乳糖喂养的大鼠以及视网膜周细胞醛糖还原酶水平升高的正常和转基因小鼠中进行。通过阐明这种己糖相关氧化应激的来源，确定醛糖还原酶改变眼部b-FGF、IGF和tgf - β水平及其相关信号通路和基因表达的具体机制，可以为白内障和糖尿病性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。