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Regulation of eNOS by S-Nitrosylation in Diet Associated Erectile Dysfunction

S-亚硝基化对饮食相关勃起功能障碍中 eNOS 的调节

基本信息

批准号：
8956998
负责人：
Justin David LaFavor
金额：
$ 5.42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2017-09-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8956998
关键词：
Active Sites Address Animal Sources Binding Biological Assay Consumption Coupling Cysteine Data Dependence Development Diamide Diet Dietary Intervention Dithiothreitol Dose Dyslipidemias Endothelial Cells Environment Erectile dysfunction Etiology Event Fatty Acids Fatty acid glycerol esters Fellowship Fibrosis Genetic Glutathione Disulfide Glutathione Reductase Health Immunoprecipitation Impairment Individual Insulin Resistance Intake Intraperitoneal Injections Knockout Mice Link Maintenance Mass Spectrum Analysis Measurement Measures Mediating Mediator of activation protein Metabolic syndrome Methods Modeling Modification Molecular Morphology Mus Nerve Nitric Oxide Nitric Oxide Synthase Nutrient Obesity Operative Surgical Procedures Oxidants Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Penile Erection Physiological Post-Translational Protein Processing Prevention Protein S Proteins Proteome Proteomics Quality of life Rattus Reactive Oxygen Species Reducing Agents Regulation Research Rodent Role SKIL gene Signal Pathway Signal Transduction Signaling Molecule Site Staining method Stains Stimulus Sucrose Sulfhydryl Compounds Superoxides System Techniques Thioredoxin Tissues Training United States Vegetable Oils Western Blotting base dimer disulfide bond experience feeding genetic manipulation human NOS3 protein in vivo inhibitor/antagonist light microscopy mTOR protein monomer mouse model novel strategies nutrition penis protein structure function public health relevance response sugar vector western diet

项目摘要

PROJECT SUMMARY A diet abundant in sugar and fats derived from animal sources and cheap vegetable oils has been termed the "Western diet". Consumption of the Western diet is now prevalent in the United States and has been spreading throughout the world over the past 15 years. Consumption of a Western style diet is implicated in the etiology of erectile dysfunction (ED), a condition strongly associated with reduced quality of life. Nitric oxide is a primary mediator of penile erection, which is produced by nitric oxide synthase. Under conditions of excessive oxidative stress, endothelial nitric oxide synthase (eNOS) may become uncoupled, whereby superoxide is produced rather than nitric oxide, which propagates further oxidative stress. It is thought that eNOS coupling status is regulated by adequate presence of co-factors and substrates. However, recent data indicate that eNOS uncoupling and dysfunctionality may be promoted by S-nitrosylation, which may be dependent on an oxidative shift in cellular redox state. Additionally, the mammalian target of rapamycin (mTOR) is a cellular signaling molecule that may induce oxidative stress in response to excessive fat and sugar consumption. The primary hypothesis of this proposal is that an oxidative shift in the penile redox environment, mediated by mTOR- dependent nutrient signaling in response to the Western diet promotes erectile dysfunction due to eNOS dysregulation via excessive S-nitrosylation induced by impairment of the denitrosylation system. Specific aims for the proposal are: 1) to determine if Western diet-induced ED is mediated by an oxidative shift in redox state dependent upon mTOR signaling; 2) to determine if the mTOR dependent shift in redox state exerts alteration of S-nitrosylation; 3) to determine if regulation of S-nitrosylation controls erectile function in a diet-dependent manner. The proposed research plan includes the use of a Western style rodent diet in combination with pharmacologic, molecular, proteomic, and physiological studies. These studies utilize the Western diet in combination with pharmacologic shifts in redox state, inhibition of mTOR, and genetic manipulation of proteins that regulate denitrosylation. Molecular studies proposed include assessment of protein structure, function, and post-translational modifications influencing eNOS, the mTOR signaling pathway, and the proteins that regulate cellular S-nitrosylation. Proteomic studies proposed include assessment of S-nitrosylation status of the penile proteome, as well as S-nitrosylation of individual thiol groups of penile eNOS. Molecular and proteomic studies will be enriched by physiologic erectile function measurements in response to these perturbations. The proposed studies include the use of a genetic mouse model where the regulation of S-nitrosylation is manipulated, and a rat model where the regulation of S-nitrosylation is manipulated specifically in the penis. It is anticipated that the findings of this proposal will provide greater understanding of molecular events leading to Western diet associated ED, and provide a basis for enhanced treatment.

项目总结