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

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) 个体和所有 T1D 动物模型心肌收缩力下降的主要原因。导致这种缺陷的蛋白质之一是 2 型兰尼碱受体 (RyR2)，Ca2+ 是通过该通道离开肌浆网以实现收缩的。迄今为止，T1D 期间 RyR2 功能障碍的精确分子机制仍不清楚。我们的实验室最近发现链脲佐菌素 (STZ) 诱导的糖尿病大鼠心脏功能失调的 RyR2 在选定的碱性残基上含有羰基加合物。用吡哆胺治疗糖尿病大鼠以清除反应性羰基物质，可以减弱糖尿病引起的 RyR2 功能障碍，使心肌细胞兴奋-收缩耦合和心肌收缩力正常化。运动训练 STZ 糖尿病大鼠还减少了反应性羰基物质的产生，减少了 RyR2 上羰基加合物的形成，恢复了心室肌细胞的兴奋-收缩耦合，并减弱了糖尿病引起的心肌收缩力的降低。这些新数据表明，长寿命 RyR2 的羰基加合物（羰基化）的形成具有重要的功能，而不是糖尿病的附带现象。我们的中心假设是“糖尿病导致 RyR2 上关键氨基酸残基的羰基化，导致 RyR2 功能障碍、兴奋-收缩耦合受损和心力衰竭。”我们将使用细胞培养和 STZ 糖尿病大鼠模型来 (i) 阐明糖尿病期间羰基加合物改变 RyR2 功能的分子机制，以及 (ii) 确定吡哆胺治疗和运动训练减轻 T1D 期间 RyR2 功能障碍的分子机制。该项目的数据将为了解这组未充分研究的细胞氧化剂（反应性羰基物质）如何损害 RyR2 的活性，从而导致 T1D 期间兴奋-收缩耦合缺陷和心肌收缩力降低提供有价值的机制见解。由于蛋白质的羰基应激和羰基化也发生在 2 型糖尿病和代谢综合征中，因此从该项目中获得的知识也可用于设计新的治疗策略来管理这些个体的心肌功能障碍。简单总结：心力衰竭是糖尿病患者发病和死亡的主要原因。然而，这种心力衰竭的原因尚不完全清楚。该项目旨在进一步了解糖尿病患者心脏衰竭的原因。这项研究尤其重要，因为它可以帮助开发更新的治疗策略/选择，以改善糖尿病患者的生活质量并控制糖尿病护理不断上升的经济成本，估计每年超过 1320 亿美元。