Strategies and functional outcomes of enhancing in vivo production of soluble rage isoforms

增强可溶性愤怒亚型体内产生的策略和功能结果

• 批准号: 9505899
• 负责人: JACOB M HAUS
• 金额: $ 60.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505899
• 关键词: Acetylation; Acetylcholine; Acute; Adult; Advanced Glycosylation End Products; Aerobic Exercise; Affect; Agonist; Animal Model; Appearance; Atherosclerosis; Behavior; Binding; Biological Markers; Biology; Biopsy; Blood; Blood Circulation; Blood Vessels; Calcium; Calcium Signaling; Caring; Cells; Chronic; Cleaved cell; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Deacetylation; Development; Diabetes Mellitus; Disease; Disintegrins; Exercise; Family; Gene Expression; Generations; Goals; Health; Healthcare Systems; Homologous Gene; Human; Individual; Inflammation; Inflammatory; Interruption; Ligand Binding; Ligands; Lysine; Maintenance; Mediating; Medical; Metabolic; Metabolism; Metalloproteases; Microdialysis; Microvascular Dysfunction; Modeling; Muscle; Muscle Contraction; Muscle Fibers; Needles; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Oral; Periodicity; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Plasma; Prevention; Prevention strategy; Production; Protein Isoforms; Public Health; RARB gene; RNA Interference; Rage; Randomized; Recombinants; Research; Resolution; Retinoids; Sampling; Serine; Signal Transduction; Skeletal Muscle; Source; Stimulus; Testing; Therapeutic; Thinness; Tissues; Up-Regulation; Vascular Diseases; Vasodilation; Work; cardiometabolism; cardiorespiratory fitness; care burden; cohort; control trial; cost effective; diabetes management; diabetic; expectation; experimental study; functional outcomes; gamma secretase; glucose tolerance; impaired glucose tolerance; improved; in vivo; innovation; insight; insulin sensitivity; novel; pressure; prevent; protective effect; protein expression; receptor for advanced glycation endproducts; response; social; standard care; treatment strategy

Project Summary /Abstract Activation of RAGE (receptor of advanced glycation endproducts (AGEs)), via binding of AGEs and other ligands, modulates the development and progression of diabetic complications through persistent and cyclic activation of nuclear factor-ΚB. Targeting RAGE directly as a therapeutic strategy has largely been unsuccessful. However, RAGE signaling can be interrupted, in vivo, by ADAM10 (a disintegrin and metalloproteinase 10) directed proteolytic cleavage of the RAGE ectodomain, and thus creating a soluble isoform of RAGE (sRAGE) that is released from the cell and appears into the circulation. Maintaining high levels of circulating sRAGE is advantageous as sRAGE will sequester RAGE ligands and prevent RAGE cell signaling. Our long-term goal is to identify strategies for the prevention and treatment of diabetic complications. Using aerobic exercise, we have elucidated a mechanism for ADAM10 upregulation to increase RAGE shedding. Aerobic exercise presents a unique model for mechanistic study of RAGE shedding as muscle contraction provides stimuli for tissue remodeling and resolution of the metabolic milieu that drives inflammation. Our central hypothesis is that skeletal muscle is a quantitatively important source of sRAGE appearance in the circulation and maintenance of healthy levels of total sRAGE promotes cardiometabolic health. The rationale is that once the mechanisms of ADAM10 activation and sRAGE generation are elucidated, progress towards the prevention and treatment of diabetic complications may be possible. Compelled by noteworthy preliminary data, we propose three specific aims to pursue our central hypothesis: (1) we will test the effects of acute and chronic exercise in generating sRAGE isoforms (2) we will determine the effects of acitretin therapy on RAGE mediated inflammation and (3) we will explore new protective effects of sRAGE in the microvasculature. The work is innovative because the study of RAGE ectodomain shedding in human skeletal muscle challenges the current understanding of AGE/RAGE biology and the known behavior of ADAM10 activity. At the completion of these studies, it is our expectation that we will have identified a novel mechanism of ADAM10 activation and an important tissue source of sRAGE production. Ultimately, such an insight has the potential to improve the prevention and therapeutic management of diabetes and its complications, thus reducing the financial and social burden that affects the ~347 million people worldwide with diabetes.

项目总结/摘要 通过结合晚期糖基化终产物（AGEs）和其他糖基化终产物（AGEs）受体激活AGEs 配体，调节糖尿病并发症的发展和进展，通过持续和循环 激活核因子-ΚB B。直接靶向抗肿瘤作为一种治疗策略， 不成功。然而，在体内，ADAM 10（一种去整合素， 金属蛋白酶10）指导的胞外域的蛋白水解切割，从而产生可溶性的 从细胞中释放出来并进入循环系统的一种β-淀粉样蛋白（β-淀粉样蛋白）的亚型。保持高 循环中的唾液酸水平是有利的，因为唾液酸将螯合唾液酸配体并防止唾液酸细胞增殖。 发信号。我们的长期目标是确定预防和治疗糖尿病并发症的策略。 通过有氧运动，我们阐明了ADAM 10上调以增加运动量的机制。 脱落有氧运动为研究肌肉脱落机制提供了一个独特的模型 收缩为组织重塑和代谢环境的解决提供了刺激， 炎症我们的中心假设是骨骼肌是一个重要的脂肪来源 出现在循环和维持健康水平的总sediment促进心脏代谢 健康其基本原理是，一旦ADAM 10激活和分泌物产生的机制被阐明， 阐明，对糖尿病并发症的预防和治疗的进展可能是可能的。 在值得注意的初步数据的推动下，我们提出了三个具体目标来追求我们的中心假设： (1)我们将测试急性和慢性运动对产生sx 2亚型的影响（2），我们将确定 阿维A治疗对炎症介导的影响;（3）我们将探索新的保护作用 微血管中的粘液。这项工作是创新性的，因为研究的细胞外结构域脱落， 人类骨骼肌挑战了目前对AGE/AGEs生物学的理解， ADAM 10活性在这些研究完成后，我们希望我们能找到一部小说， ADAM 10激活的机制和分泌唾液的重要组织来源。最终，这样一个 洞察力有可能改善糖尿病的预防和治疗管理， 并发症，从而减轻影响全球约3.47亿人的经济和社会负担， 糖尿病