Role of Hydrogen Sulfide Depletion in Western Diet-Induced Erectile Dysfunction

硫化氢消耗在西方饮食引起的勃起功能障碍中的作用

基本信息

批准号：
10011566
负责人：
Justin David LaFavor
金额：
$ 15.94万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2022-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011566
关键词：
Address Affect American Animal Sources Animals Antioxidants Anxiety Award Basic Science Binding Bioenergetics Biological Biological Assay Biotin Blood Vessels Cell Fractionation Chronic Clinical Trials Collaborations Custom Cyclic GMP-Dependent Protein Kinases Cystathionine Cysteine Data Development Diet Dimerization Distress Doctor of Philosophy Dose Down-Regulation Effectiveness Endothelium Enzymes Erectile dysfunction Exercise Exposure to Fatty acid glycerol esters Free Radicals Genetic Genetic Transcription Glutathione Reductase Health Health Care Costs Human Hydrogen Peroxide Hydrogen Sulfide Injection of therapeutic agent International Investigation Lead Life Lyase Mass Spectrum Analysis Measurement Measures Mediating Mental Depression Mentors Mentorship Methodology MicroRNAs Microdialysis Modification Molecular Mus Mutation NOS3 gene Nerve Neurons Nitric Oxide Nitric Oxide Synthase Nuclear Nutrient Operative Surgical Procedures Oral Oxidation-Reduction Pathway interactions Patients Penile Prosthesis Predisposition Prevalence Principal Investigator Production Property Protein Isoforms Proteins Proteome Quality of life Reactive Oxygen Species Relaxation Reporting Research Resource Development Rest Risk Factors Rodent Rodent Model Role Science Scientist Signal Transduction Societies Sulfhydryl Compounds Superoxides Techniques Testing Tissues Training Treatment Cost United States Untranslated RNA Urology Vegetable Oils Western Blotting cardiometabolism career development experience feeding in vivo inhibitor/antagonist lifestyle factors medical schools men modifiable risk mouse model neurotransmission novel therapeutic intervention penis phosphoric diester hydrolase physical inactivity post-doctoral training preservation pressure prevent programs response satisfaction skills sugar sulfhydration western diet

项目摘要

Project Summary/Abstract This proposal aims to provide advanced career development and training to the applicant. The principal investigator (PI) has previously received PhD training in bioenergetics and exercise science, and has received postdoctoral training in urology under the mentorship of Dr. Arthur Burnett, a recognized leader in the basic science of erectile dysfunction. The PI will receive further training from Dr. Solomon Snyder, an internationally recognized leader in neurotransmission with a strong track record of training successful scientists. The proposed training plan will provide continued refinement of the PI’s scientific, technical, and professional skills and aid in his transition to independence. The PI will take advantage of the vast training and professional development resources at the Johns Hopkins School of Medicine. The proposed research seeks to identify the potential role of hydrogen sulfide (H2S) as a regulator of erectile function. We have previously established a rodent model of Western diet-induced erectile dysfunction (ED). Initial investigations suggest that excessive protein nitrosylation (binding of nitric oxide (NO) to protein thiols) accelerates the ED development in response to the Western diet. The Western diet also diminishes production of hydrogen sulfide (H2S) in erectile tissue. Our research team has previously demonstrated that H2S exerts cell signaling through protein sulfhydration (binding of H2S to thiols), which often opposes the effects of nitrosylation. Use of a recently developed technique to measure in vivo reactive oxygen species indicates that the Western diet increases penile free radical production, which is accelerated by nitrosylation. H2S has previously been reported to have antioxidant properties and that signaling by sulfhydration may protect against damaging effects of excessive amounts of free radicals. Thus, we hypothesize that diminished H2S production resulting from the Western diet is a key factor in the development of ED. In this proposal, we are aiming to understand how H2S affects the redox state of the penis by examining levels of enzymes that produce H2S, measuring penile free radicals, and investigating sulfhydration signaling in pathways that regulate antioxidant capacity. We are also aiming to understand how the interplay between H2S action and nitrosylation impacts protein kinase G signaling and erectile function. To address these aims, we will use genetically modified mouse models of diminished H2S production, enhanced H2S production, excessive nitrosylation, and altered protein kinase G signaling. Mice will be exposed to a Western diet, and oral therapies to enhance H2S production will be investigated as a potential therapy to treat ED.