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：
9430499
负责人：
Justin David LaFavor
金额：
$ 9.84万
依托单位：
JOHNS HOPKINS 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 2018-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9430499
关键词：
Address Affect American Animal Sources Animals Antioxidants Anxiety Award Basic Science Binding Bioenergetics 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 Enzymes Erectile dysfunction Exercise 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 career development dimer 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 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.

项目概要/摘要该提案旨在为申请人提供先进的职业发展和培训。研究者（PI）之前曾接受过生物能量学和运动科学方面的博士培训，并已获得在泌尿外科领域公认的领导者 Arthur Burnett 博士的指导下接受博士后培训 PI 将接受国际知名人士所罗门·斯奈德 (Solomon Snyder) 博士的进一步培训。神经传递领域公认的领导者，在培训成功科学家方面拥有良好的记录。拟议的培训计划将持续完善 PI 的科学、技术和专业技能并帮助他过渡到独立。 PI 将利用大量的培训和专业知识。约翰霍普金斯大学医学院的开发资源。拟议的研究旨在确定硫化氢 (H2S) 作为调节剂的潜在作用我们之前已经建立了西方饮食引起的勃起功能障碍的啮齿动物模型。 (ED) 初步研究表明蛋白质过度亚硝基化（一氧化氮 (NO) 与蛋白质结合）。硫醇）会加速 ED 的发展，以应对西方饮食。我们的研究小组之前已经证明，勃起组织中会产生硫化氢（H2S）。 H2S 通过蛋白质硫化作用（H2S 与硫醇结合）发挥细胞信号传导作用，这通常会阻碍使用最近开发的技术来测量体内活性氧。表明西方饮食会增加阴茎自由基的产生，而亚硝基化会加速自由基的产生。此前已有报道称 H2S 具有抗氧化特性，并且通过硫化作用发出的信号可能防止过量自由基的破坏性影响因此，我们遭受的伤害减少了。西方饮食产生的 H2S 是 ED 发生的关键因素。旨在通过检查酶的水平来了解 H2S 如何影响阴茎的氧化还原状态产生 H2S，测量阴茎自由基，并研究途径中的硫化信号传导我们还致力于了解 H2S 作用与抗氧化能力之间的相互作用。亚硝基化会影响蛋白激酶 G 信号传导和勃起功能。为了实现这些目标，我们将使用。 H2S 产生减少、H2S 产生增加、过量的转基因小鼠模型亚硝基化和改变的蛋白激酶 G 信号转导小鼠将接受西方饮食和口服疗法。增强 H2S 产生的方法将作为治疗 ED 的潜在疗法进行研究。