Evaluation of Endothelial Hyperglycemia-Driven Alterations During Type 2 Diabetes

2 型糖尿病期间内皮高血糖驱动变化的评估

• 批准号: 9322612
• 负责人: Brian Robert Hoffmann
• 金额: $ 10.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322612
• 关键词: Acetylcholine; Affect; Agonist; Area; Automobile Driving; Biochemical; Bioinformatics; Biological Assay; Biology; Blood Vessels; Cardiovascular Diseases; Cell physiology; Cell surface; Clinical; Complex; Coronary Arteriosclerosis; Coupled; Data; Development; Diabetes Mellitus; Diagnosis; Educational workshop; Endothelial Cells; Endothelium; Ensure; Epidemic; Equilibrium; Evaluation; Exposure to; Fostering; Functional disorder; Funding; Gene Expression; Glucose; Glycoproteins; HTR2A gene; Homology Modeling; Human; Hyperglycemia; Impairment; Inflammatory; Ions; K-Series Research Career Programs; Lead; Mass Spectrum Analysis; Measures; Medicine; Membrane; Membrane Glycoproteins; Mentors; Modeling; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Ontology; Outcome; Outcomes Research; Pathway interactions; Patients; Peripheral Vascular Diseases; Pharmacology; Phenotype; Phosphorylation; Physiological; Physiology; Principal Investigator; Production; Prostaglandins; Protein Glycosylation; Proteomics; Protocols documentation; Rattus; Receptor, Angiotensin, Type 1; Regulation; Research; Research Design; Research Personnel; Research Proposals; Risk; Sequence Homology; Signal Pathway; Signal Transduction; Site; Supervision; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Training; Tube; United States; Validation; Vascular Diseases; Vascular Endothelium; base; career development; clinically relevant; cohort; design; diabetic patient; experimental study; glycosylation; improved; innovation; medical specialties; mid-career faculty; mortality; multidisciplinary; new therapeutic target; novel; professor; programs; protein expression; public health relevance; receptor; response; signal processing; success

 DESCRIPTION (provided by applicant): Diabetes currently afflicts approximately 25.8 million people in the United States (US) and 220 million people worldwide. Type 2 diabetes mellitus (T2DM) accounts for ~95% of all diagnosed cases in the US, among which cardiovascular disease is the leading cause of mortality. Vascular dysfunction, leading to increased risk of coronary artery disease and peripheral vascular disease, remains an important clinical problem in diabetic patients. Hyperglycemia is a major causative factor of T2DM contributing to vascular dysfunction, however, there is a large gap of mechanistic studies in this area. This proposal evaluates the underlying hyperglycemia- induced alterations in the endothelium glycoproteome that lead to changes in important homeostatic signaling pathways, such as the AT1R and HTR2A signaling pathways, and result in vascular dysfunction. The aims of this proposal utilize innovative glycoproteome and phosphoproteome enrichment, sensitive mass spectrometry technology, and physiologically relevant functional tests to explore hyperglycemia-induced protein glycosylation at the cell surface (Aim 1), alterations of the synergistic balance of intracellular O-GlcNAcylation and phosphorylation (Aim 2), and subsequent alterations in important homeostatic signaling pathways leading to vascular dysfunction (Aim 3). In order to do this, the applicant requires protected time for supervised career development in bioinformatics, proteomics as applied to physiological systems, vascular biology, clinically relevant human cohort experimentation, and professional development under the direction of Dr. Andrew Greene (Professor of Physiology-MCW) and co-mentor Dr. Michael Widlansky (Associate Professor of Medicine and Pharmacology-MCW). This research proposal and career development modules will assist in fostering the Principal Investigator in his independence such that he can lead a research program aimed at examining causal factors in T2DM. The mentored career development award will further the candidate's training in bioinformatics processing for signal pathway ontology analyses, along with continued training in proteomics analysis applied to complex systems. The applicant will also receive extensive training in vascular biology as it relates to functional studies of T2DM rat models and vessels from T2DM patients. The training agenda includes lab-based training (MCW), clinical training (MCW/Froedtert & CTSI), specialty training in external labs, coursework, and professional development seminars/workshops. This multi-disciplinary training will ensure the ability of the applicant to design, perform, troubleshot, and interpret experiments independently. Outcomes of research proposal described here will provide direct evidence to confirm or refute the fundamental hypothesis that hyperglycemia-induced glycosylation is driving specific alterations leading to vascular dysfunction in T2DM and in combination with the professional career development will foster a smooth transition of the candidate to an independently funded investigator.

 描述（由申请人提供）：糖尿病目前困扰着美国（US）约2580万人和全球2.2亿人。2型糖尿病（T2 DM）占美国所有确诊病例的约95%，其中心血管疾病是死亡的主要原因。血管功能障碍，导致冠状动脉疾病和外周血管疾病的风险增加，仍然是糖尿病患者的重要临床问题。高血压是导致2型糖尿病血管功能障碍的主要原因之一，但其机制研究仍存在较大空白。该提案评估了内皮糖蛋白组中潜在的高血糖诱导的改变，这些改变导致重要的稳态信号传导途径（如AT 1 R和HTR 2A信号传导途径）的变化，并导致血管功能障碍。本提案的目的是利用创新的糖蛋白组和磷酸蛋白组富集、灵敏的质谱技术和生理学相关功能测试来探索高血糖诱导的细胞表面蛋白质糖基化（目的1）、细胞内O-GlcNAc酰化和磷酸化协同平衡的改变（目的2），以及随后导致血管功能障碍的重要稳态信号通路的改变（Aim 3）。为了做到这一点，申请人需要在生物信息学，蛋白质组学应用于生理系统，血管生物学，临床相关的人类队列实验和专业发展的指导下的监督职业发展的时间保护安德鲁格林博士（生理学-MCW教授）和共同导师迈克尔Widlansky博士（医学和药理学-MCW副教授）。本研究提案和职业发展模块将有助于培养主要研究者的独立性，使其能够领导旨在检查T2 DM因果因素的研究项目。导师职业发展奖将进一步培训候选人的生物信息学处理信号通路本体分析，沿着继续培训蛋白质组学分析应用于复杂系统。申请人还将接受血管生物学方面的广泛培训，因为其与T2 DM大鼠模型和T2 DM患者血管的功能研究有关。培训议程包括实验室培训（MCW），临床培训（MCW/Froedtert & CTSI），外部实验室专业培训，课程和专业发展研讨会/研讨会。这种多学科培训将确保申请人独立设计，执行，测试和解释实验的能力。本文描述的研究提案的结果将提供直接证据，以证实或反驳基本假设，即高血糖诱导的糖基化正在驱动导致T2 DM血管功能障碍的特定改变，并结合专业职业发展将促进候选人顺利过渡到独立资助的研究者。