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：
10242683
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 2024-05-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242683
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

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

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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.

项目摘要/摘要该建议旨在为申请人提供高级职业发展和培训。校长调查员（PI）以前曾接受过生物能力和运动科学的博士学位培训，并已收到亚瑟·伯内特（Arthur Burnett）博士的心态下的泌尿外科博士后培训，这是基本的公认领导者勃起功能障碍的科学。 PI将获得国际上所罗门·斯奈德（Solomon Snyder）博士的进一步培训公认的神经传递领导者，并具有培训成功科学家的良好记录。拟议的培训计划将持续改进PI的科学，技术和专业技能并帮助他过渡到独立。 PI将利用庞大的培训和专业人士约翰·霍普金斯医学院的开发资源。拟议的研究旨在确定硫化氢（H2S）作为调节剂的潜在作用勃起功能。我们以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，过量的蛋白质亚硝基化（一氧化氮（NO）与蛋白质的结合硫醇）响应西方饮食加速了ED的发展。西方饮食也减少勃起组织中硫化氢（H2S）的产生。我们的研究团队以前已经证明 H2S通过蛋白质硫酸盐（H2S与硫醇的结合）发挥细胞信号，这通常相反亚硝基化的作用。使用最近开发的技术来测量体内活性氧表明西方饮食增加了阴茎自由基产生，这是通过亚硝基化加速的。先前据报道H2S具有抗氧化特性，通过硫磺信号传导可能防止过量自由基的损害影响。那我们假设这减少了西方饮食产生的H2S产量是ED发展的关键因素。在这个建议中，我们旨在通过研究酶的水平来了解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硫磺信号传导调节抗氧化能力。我们还旨在了解H2S动作与硝基化会影响蛋白激酶G信号传导和勃起功能。为了解决这些目标，我们将使用 H2S生产减少的转基因小鼠模型，增强的H2S生产超过硝基化和改变的蛋白激酶G信号传导。小鼠将暴露于西方饮食和口服疗法为了增强H2S的生产，将作为治疗ED的潜在疗法进行研究。