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A Role for Advanced Glycation End-Products in Diabetic Lung Injury

高级糖基化终产物在糖尿病肺损伤中的作用

基本信息

批准号：
7660367
负责人：
JUDSON M ENGLERT
金额：
$ 4.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2013-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7660367
关键词：
A549 Advanced Glycosylation End Products Affinity Age Alveolar Animals Asbestos Asbestosis Atherosclerosis Basement membrane Binding Biological Assay Breathing Cell Line Cells Collagen Collagen Type IV Crocidolite Asbestos Deposition Development Diabetes Mellitus Diabetic mouse Disease Dust Environmental Exposure Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Epithelial Epithelial Cells Experimental Models Fiber Fibrosis Freezing Hamman-Rich syndrome Healed Histologic Human Hydroxyproline Impaired wound healing Injury Kidney Diseases Knockout Mice Ligands Lung Lung diseases Measures Mediating Modeling Morbidity - disease rate Neuropathy Occupational Pathogenesis Pathology Patients Play Pneumoconiosis Population Predisposition Proteins Pulmonary Fibrosis RNA Reverse Transcriptase Polymerase Chain Reaction Risk Role Saline Sampling Serum Severities Severity of illness Signal Transduction Silicon Dioxide Small Interfering RNA Structure of parenchyma of lung Symptoms Testing Tissues Transfection Western Blotting Wild Type Mouse Wound Healing diabetic effective therapy glycemic control healing knock-down lung injury mortality particle prevent receptor response time interval titanium dioxide wound

项目摘要

DESCRIPTION (provided by applicant): Pneumoconioses are occupational lung diseases caused by the inhalation of dust fibers/particles such as asbestos and silica. Experimental models of asbestosis recapitulate the salient features of idiopathic pulmonary fibrosis (IPF), a debilitating disease with both high morbidity and mortality due to a lack of effective therapies. Recent epidemiological studies have suggested that diabetics are at increased risk of developing idiopathic pulmonary fibrosis. This has led our lab to hypothesize that diabetics are at increased risk of developing pulmonary disease after environmental exposures. As the diabetic population increases at an alarming rate it is important to determine the mechanism by which diabetics are more susceptible to pulmonary injury so that it can be better prevented and treated. Recently our lab has implicated loss of the receptor for advanced glycation end-products (RAGE) as a key pathogenic step in the development of pulmonary fibrosis. This receptor has also been implicated in numerous other diabetic pathologies including neuropathy, atherosclerosis, and nephropathy. This has led us to investigate its potential role in increasing diabetics susceptibility to pulmonary injury. Preliminary studies have shown that aged diabetic mice have a loss of RAGE in their lung tissue. This could provide a potential mechanism by which diabetics are more likely to develop pulmonary fibrosis. This project will focus on the mechanisms by which RAGE promotes wound healing and prevents de-epithelialization and subsequent disease. We will also investigate the role that increased advanced glycation end-products (AGEs) play in the disease pathogenesis. Ultimately, we hope to determine if clearing RAGE ligands by use of a non-signaling decoy receptor, sRAGE, protects against the fibrotic response after asbestos exposure. This project will investigate the possibility that diabetics are at increased risk of developing pulmonary fibrosis after being exposed to occupational dust particles. It will provide a better understanding of how the disease develops which will help us develop better ways to prevent and treat the disease and its symptoms.

描述（由申请人提供）：肺尘埃沉着病是一种职业性肺部疾病，由吸入石棉和二氧化硅等粉尘纤维/颗粒引起。石棉沉滞症的实验模型概括了特发性肺纤维化（IPF）的显著特征，特发性肺纤维化是一种由于缺乏有效治疗而具有高发病率和死亡率的衰弱性疾病。最近的流行病学研究表明，糖尿病患者发生特发性肺纤维化的风险增加。这使得我们的实验室假设糖尿病患者在环境暴露后患肺部疾病的风险增加。随着糖尿病人群以惊人的速度增加，重要的是要确定糖尿病患者更容易受到肺损伤的机制，以便更好地预防和治疗。最近，我们的实验室已经暗示晚期糖基化终末产物受体（AGEs）的丢失是肺纤维化发展的关键致病步骤。该受体还涉及许多其他糖尿病病理，包括神经病变、动脉粥样硬化和肾病。这使我们研究其在增加糖尿病患者对肺损伤的易感性中的潜在作用。初步研究表明，老年糖尿病小鼠的肺组织中有一个损失。这可能提供了一个潜在的机制，糖尿病患者更有可能发展为肺纤维化。该项目将重点研究骨胶原促进伤口愈合和防止去上皮化及后续疾病的机制。我们还将研究增加的晚期糖基化终产物（AGEs）在疾病发病机制中的作用。最后，我们希望确定是否通过使用一种非信号诱饵受体，sodium，清除β配体，防止石棉暴露后的纤维化反应。该项目将调查糖尿病患者在暴露于职业粉尘颗粒后患肺纤维化风险增加的可能性。它将提供对疾病如何发展的更好理解，这将有助于我们开发更好的方法来预防和治疗疾病及其症状。