Role of Ryanodine Receptors in Diabetic Cadiomyopathy

兰尼定受体在糖尿病心肌病中的作用

基本信息

批准号：
7196790
负责人：
KESHORE R BIDASEE
金额：
$ 36.75万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7196790
关键词：
Address Adhesions Adolescent Adult Amines Amino Acids Animal Model Animals Arginine Arrhythmia Attenuated Binding Biological Assay Blood Vessels Ca(2+)-Transporting ATPase Caffeine Calcium Calmodulin Cardiac Caring Cells Charge Child Complex Condition Confocal Microscopy Contracts Coupling Cultured Cells Cyclic ADP-Ribose Data Defect Depressed mood Development Diabetes Mellitus Dissociation Echocardiography Economics Enzymes Epidemic Etiology Exercise Exhibits FKBP1B gene Frequencies Functional disorder Glutamine Heart Heart failure Histidine Impairment In Vitro Incubated Individual Insulin-Dependent Diabetes Mellitus Knowledge Laboratories Left Life Ligands Lysine M-Mode Echocardiography Mass Spectrum Analysis Measurement Measures Mediating Membrane Metabolic syndrome MgATP Modeling Molecular Morbidity - disease rate Muscle Cells Mutation Myocardial Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Other Finding Oxidants Patients Phosphorylation Physiologic intraventricular pressure Plasma Probability Production Proteins Pyridoxamine Pyruvaldehyde Quality of life Rate Rattus Recombinants Research Research Personnel Role RyR2 Ryanodine Ryanodine Receptor Calcium Release Channel SERCA2a Sarcoplasmic Reticulum Semicarbazides Site Site-Directed Mutagenesis Streptozocin Stress Syndrome Testing Text Therapeutic Time Tissues Training Ventricular Western Blotting Work adduct amine oxidase carbamylhydrazine cost design diabetic diabetic cardiomyopathy diabetic rat hemodynamics improved in vivo insight mortality mutant novel therapeutics programs prototype response stem sudden cardiac death type I and type II diabetes

Address Adhesions Adolescent Adult Amines Amino Acids Animal Model Animals Arginine Arrhythmia Attenuated Binding Biological Assay Blood Vessels Ca(2+)-Transporting ATPase Caffeine Calcium Calmodulin Cardiac Caring Cells Charge Child Complex Condition Confocal Microscopy Contracts Coupling Cultured Cells Cyclic ADP-Ribose Data Defect Depressed mood Development Diabetes Mellitus Dissociation Echocardiography Economics Enzymes Epidemic Etiology Exercise Exhibits FKBP1B gene Frequencies Functional disorder Glutamine Heart Heart failure Histidine Impairment In Vitro Incubated Individual Insulin-Dependent Diabetes Mellitus Knowledge Laboratories Left Life Ligands Lysine M-Mode Echocardiography Mass Spectrum Analysis Measurement Measures Mediating Membrane Metabolic syndrome MgATP Modeling Molecular Morbidity - disease rate Muscle Cells Mutation Myocardial Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Other Finding Oxidants Patients Phosphorylation Physiologic intraventricular pressure Plasma Probability Production Proteins Pyridoxamine Pyruvaldehyde Quality of life Rate Rattus Recombinants Research Research Personnel Role RyR2 Ryanodine Ryanodine Receptor Calcium Release Channel SERCA2a Sarcoplasmic Reticulum Semicarbazides Site Site-Directed Mutagenesis Streptozocin Stress Syndrome Testing Text Therapeutic Time Tissues Training Ventricular Western Blotting Work adduct amine oxidase carbamylhydrazine cost design diabetic diabetic cardiomyopathy diabetic rat hemodynamics improved in vivo insight mortality mutant novel therapeutics programs prototype response stem sudden cardiac death type I and type II diabetes

展开

项目摘要

DESCRIPTION (provided by applicant): Perturbation of intracellular Ca2+ cycling is a primary cause for the depressed myocardial contractility in individuals with type 1 diabetes (T1D) and in all animal models of T1D. One of the proteins that contribute to this defect is type 2 ryanodine receptor (RyR2), the channel through which Ca2+ leave the sarcoplasmic reticulum to effect contraction. To date, precise molecular mechanisms responsible for RyR2 dysfunction during T1D remain unknown. Our laboratory recently found that dysfunctional RyR2 from streptozotocin (STZ)-induced diabetic rat hearts contain carbonyl adducts on select basic residues. Treatment of diabetic rats with pyridoxamine to scavenge reactive carbonyl species blunted diabetes-induced dysfunction of RyR2, normalize myocyte excitation-contraction coupling and myocardial contractility. Exercise training STZ-diabetic rats also reduced production of reactive carbonyl species, decreased formation of carbonyl adducts on RyR2, restored excitation-contract coupling in ventricular myocytes and blunted diabetes- induced reduction in myocardial contractility. These new data suggest that formation of carbonyl adducts (carbonylation) of long-lived RyR2 is functionally important and not an epiphenomenon of diabetes. Our central hypothesis is "diabetes leads to carbonylation of critical amino acid residues on RyR2, causing RyR2 dysfunction, impairment of excitation-contraction coupling and heart failure." We will use cell culture and STZ-diabetic rat models to (i) elucidate molecular mechanisms by which carbonyl adducts alter RyR2 function during diabetes, and (ii) determine molecular mechanisms by which pyridoxamine treatment and exercise training attenuate RyR2 dysfunction during T1D. Data from this project will provide valuable mechanistic insights into how this group of understudied cellular oxidants (reactive carbonyl species) impairs the activity of RyR2, leading to defective excitation-contraction coupling and reduced myocardial contractility during T1D. Since carbonyl stress and carbonylation of proteins also occurs in type 2 diabetes and metabolic syndrome, knowledge gained from this project could also be useful in designing newer therapeutic strategies for management of myocardial dysfunction in these individuals as well. Lay summary: Heart failure is a primary cause of morbidity and mortality in diabetic patients. However, the cause of this heart failure is not fully understood. This project is designed to further our understanding as to why the heart fails in individuals with diabetes. This research is especially important since it could help in the development of newer therapeutic strategies/options to improve the quality of life of diabetic patients and control the escalating economic cost of diabetes care, which is estimated to be in excess of $132 billion annually.

描述（由申请人提供）：细胞内Ca2+循环的扰动是1型糖尿病（T1D）和所有T1D动物模型中心肌收缩性抑郁症的主要原因。有助于这种缺陷的蛋白质之一是2型ryanodine受体（RYR2），这是Ca2+使肌浆网的通道产生收缩。迄今为止，T1D期间负责RYR2功能障碍的精确分子机制仍然未知。我们的实验室最近发现，链蛋白酶（STZ）诱导的糖尿病大鼠心脏中功能失调的RYR2在某些碱性残基上含有羰基加合物。用吡ido胺治疗糖尿病大鼠，以清除反应性羰基物种钝化的糖尿病诱导的RYR2功能障碍，使心肌细胞激发诱导偶联和心肌收缩率正常化。运动训练STZ糖尿病大鼠还减少了反应性羰基物种的产生，减少了RYR2上的羰基加合物的形成，恢复了心室心肌细胞中的激发合同偶联以及型损伤糖尿病诱导的心肌收缩性降低。这些新数据表明，长寿命RYR2的羰基加合物（羰基化）在功能上很重要，而不是糖尿病的epiphenomenon。我们的中心假设是“糖尿病会导致RYR2上关键氨基酸残基的羰基化，从而导致RYR2功能障碍，激发反应偶联和心力衰竭的损害。”我们将使用细胞培养和STZ-糖尿病大鼠模型来阐明羰基加合物在糖尿病期间改变RyR2功能的分子机制，并确定吡啶毒素治疗和运动训练减弱T1D期间RYR2功能障碍的分子机制。该项目的数据将提供有价值的机械洞察力，了解这组研究研究的细胞氧化剂（反应性羰基物种）如何损害RYR2的活性，从而导致T1D期间的兴奋性触发偶联和降低心肌收缩性。由于在2型糖尿病和代谢综合征中也出现了蛋白质的羰基胁迫和羰基化，因此从该项目中获得的知识也可能有助于设计这些个体中心肌功能障碍的新治疗策略。摘要摘要：心力衰竭是糖尿病患者发病率和死亡率的主要原因。但是，这种心力衰竭的原因尚未完全理解。该项目旨在进一步了解为什么糖尿病患者的心脏失败。这项研究尤其重要，因为它可以帮助制定更新的治疗策略/选择，以改善糖尿病患者的生活质量并控制糖尿病护理的经济成本不断上升，估计每年超过1320亿美元。