权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Deciphering ShcA-mediated ROS Production as a Novel Intervention Strategy in Diabetes Therapy

解读 ShcA 介导的 ROS 产生作为糖尿病治疗的新型干预策略

基本信息

批准号：
9193886
负责人：
FRANKLIN Alan HAYS
金额：
$ 28.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193886
关键词：
Adaptor Signaling Protein Apoptosis Apoptotic Binding Cardiovascular system Caspase Cell Culture Techniques Cell Survival Cell physiology Cells Cellular Stress Response Clinical Treatment Collagen Coupled Crystallography Cutaneous Cytochrome c Peroxidase Data Deuterium Development Diabetes Mellitus Diabetes prevention Disease Disulfides Electron Transport Energy Metabolism Family Family member Fibroblasts Foundations Future Human Hydrogen Hypertension Intervention Lipids Location Mammalian Cell Mass Spectrum Analysis Mediating Metabolic Metal Ion Binding Mitochondria Molecular Molecular Conformation Molecular Profiling Molecular Structure Myocardial Ischemia N-terminal Oxidation-Reduction Oxidative Stress Oxidoreductase Oxygen PTB Domain Pathway interactions Peripheral Peroxidases Play Post-Translational Protein Processing Production Protein Family Protein Isoforms Protein Tyrosine Kinase Proteins Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Reperfusion Injury Role Severities Signal Transduction Source Stroke Structure Sulfhydryl Compounds Superoxides System Therapeutic Wound Healing base biophysical techniques cytochrome c design diabetes mellitus therapy disulfide bond endothelial dysfunction human disease in vivo inhibitor/antagonist insight novel p66(ShcA) protein protein function receptor response small molecule therapeutic target tissue culture

项目摘要

Oxidative stress is a key determinant in the development of diabetes related microvascular and cardiovascular complications. ShcA (Src homology and collagen homology) family proteins are prototypical signaling adaptors that regulate a diverse array of cellular response pathways (e.g., tyrosine kinase (TK) signaling). One ShcA family member, p66Shc, is also a major source (~30%) of reactive oxygen species (ROS) production in mammalian cells. ShcA-mediated ROS production is a determinant of stroke size in cardiac ischemia reperfusion injury and endothelial dysfunction in diabetes (e.g., delayed cutaneous wound healing) and hypertension. The molecular basis for ShcA enzymatic function is poorly defined or unknown. This project is focused on defining how ShcA proteins function at the molecular level using a range of biophysical methods. ShcA proteins have proven difficult to study in defined systems due to their low expression profile in standard lab systems, they are conformationally variable and prone to posttranslational modification, and they interact with a broad range of proteins in vivo. The overarching hypothesis of this project is that ShcA proteins function as molecular rheostats to modulate redox state, cyt c activity, and metabolic flux in a location, conformation, and binding-dependent manner. We will investigate this hypothesis by pursuing the following Specific Aims: 1) define the enzymatic mechanism of ShcA-mediated ROS production, 2) define the functional interactions between ShcA proteins and cytochrome c, and 3) determine the structural basis for ShcA-mediated function. Outflow from this project will provide a molecular basis for ShcA function as a means to facilitate downstream development of isoform specific inhibitors of ShcA-mediated ROS production. In addition, ShcA proteins function at the crossroads of cell survival and apoptosis so this project will further define the role that ShcA proteins play in determining cellular stress response.

氧化应激是糖尿病相关微血管和心血管发展的关键决定因素