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: 9032837
• 负责人: Brian Robert Hoffmann
• 金额: $ 10.28万
• 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/9032837
• 关键词: Accounting; 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; Homology Modeling; Human; Hyperglycemia; 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; Process; 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; Surface; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Training; Tube; United States; Validation; Vascular Diseases; Vascular Endothelium; Vascular System; base; career development; clinically relevant; cohort; design; diabetic patient; glycosylation; human HTR2A protein; improved; innovation; medical specialties; mortality; novel; professor; programs; protein expression; public health relevance; receptor; research study; response; 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（由适用提供）：目前，糖尿病在美国（美国）（美国）约2580万人和全球2.2亿人患者。 2型糖尿病（T2DM）占美国所有被诊断病例的95％，其中心血管疾病是死亡率的主要原因。血管功能障碍导致冠状动脉疾病和周围血管疾病的风险增加，仍然是糖尿病患者的重要临床问题。高血糖是导致血管功能障碍的T2DM的主要结构因子，但是，该地区的机械研究差距很大。该提案评估了内皮糖蛋白酶的潜在高血糖诱导的改变，从而导致重要的稳态信号传导途径发生变化，例如AT1R和HTR2A信号通路，并导致血管功能障碍。 The aims of this Proposal utilize innovative glycoproteome and phosphoproteome enrichment, sensitive mass spectrometry technology, and physically 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稳态信号通路导致血管功能障碍（AIM 3）。这是适用的时间来监督生物信息学，蛋白质组学的职业发展，适用于物理系统，血管生物学，临床相关的人类队列实验和专业发展，并在安德鲁·格林博士（Andrew Greene）（生理学MCW教授）和同事Michael Widlansky（Michael Widlansky（Medicic of Medicic and Pharmagic Accologe and Pharmagic Accologe and Pharmagic Accology and Pharmagical Coldicor and Pharmagiate and Pressigational of Medicialology-MCW）的指导下）进行了专业发展。这项研究建议和职业发展模块将有助于培养主要研究者的独立性，以便他可以领导旨在检查T2DM中灾难性因素的研究计划。 Mendored职业发展奖将进一步为候选人在信号途径本体分析的生物信息学处理方面的培训，以及对复杂系统的蛋白质组学分析的持续培训。适用的还将接受有关血管生物学的广泛培训，因为它与T2DM大鼠模型的功能研究和T2DM患者的视频有关。培训议程包括基于实验室的培训（MCW），临床培训（MCW/Froedtert＆CTSI），外部实验室的专业培训，课程工作和专业发展半手/讲习班。这种多学科培训将确保申请人独立设计，执行，故障排除和解释实验的能力。此处描述的研究提案的结果将提供直接证据，以确认或驳斥高血糖诱导的糖基化的基本假设，即导致特定的改变，导致T2DM中的血管功能障碍，并结合职业职业发展将促进对独立资助的独立研究员的平稳转移。