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.

项目摘要 /摘要 激活愤怒（晚期糖基化终产物（年龄）的受体，通过年龄和其他结合 配体，通过持续和循环调节糖尿病并发症的发育和进展 核因子-κB的激活。直接以治疗策略为目标的愤怒已经很大程度上了 不成功。但是，ADAM10可以在体内中断愤怒信号（崩解蛋白和 金属蛋白酶10）rage e骨域的定向蛋白水解裂解，从而产生可溶性 从细胞释放并出现在循环中的愤怒（SRAGE）的同工型。保持高 循环级别的水平是有利的 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。 使用有氧运动，我们阐明了ADAM10上调的机制增加了愤怒 脱落。有氧运动提出了一个独特的模型，用于将愤怒脱落的机械研究作为肌肉 收缩为驱动的代谢环境的组织重塑和分辨率提供刺激 炎。我们的中心假设是骨骼肌肉是定量重要的Srage来源 在这种情况下的外观和维持健康水平的总SRAGE促进心脏代谢 健康。理由是，一旦ADAM10激活和Srage产生的机制是 阐明的，在预防和治疗糖尿病并发症方面的进展是可能的。 在值得注意的初步数据的强迫下，我们提出了三个特定的目标，以追求我们的中心假设： （1）我们将测试急性和慢性运动在产生SRAGE同工型的影响（2）我们将确定 丙型素治疗对愤怒介导的感染的影响，（3）我们将探索新的受保护作用 微脉管系统中的Srage。这项工作具有创新性 人类骨骼肌肉挑战了当前对年龄/愤怒生物学的理解和已知的行为 ADAM10活动。这些研究完成后，我们期望我们已经确定了一本小说 ADAM10激活的机理和SRAGE产生的重要组织来源。最终，这样的 洞察力有可能改善糖尿病的预防和治疗管理 并发症，从而减少了影响全世界约3.47亿人口的财务和社会伯恩。 糖尿病。