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

项目总结/摘要 该提案旨在为申请人提供先进的职业发展和培训。校长 研究者（PI）以前接受过生物能量学和运动科学的博士培训，并获得了 在亚瑟伯内特博士的指导下进行泌尿外科博士后培训，伯内特博士是基础医学领域公认的领导者。 勃起功能障碍的科学PI将接受所罗门斯奈德博士的进一步培训， 神经传递领域公认的领导者，在培养成功的科学家方面有着良好的记录。的 拟议的培训计划将不断完善主要研究者的科学、技术和专业技能 帮助他过渡到独立。PI将利用大量的培训和专业知识， 约翰霍普金斯医学院的发展资源。 拟议的研究旨在确定硫化氢（H2S）作为调节剂的潜在作用， 勃起功能我们先前建立了西方饮食诱导的勃起功能障碍的啮齿动物模型 （艾德）。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）加速响应西方饮食的艾德发展。西方饮食也减少了 在勃起组织中产生硫化氢（H2S）。我们的研究团队之前已经证明， H2S通过蛋白质硫水合作用（H2S与硫醇的结合）来施加细胞信号传导，这通常会对抗细胞内的蛋白质。 亚硝基化的影响。使用最近开发的技术测量体内活性氧 表明西方饮食增加阴茎自由基的产生，这是由亚硝基化加速。 H2S先前已被报道具有抗氧化特性，并且通过硫水合作用的信号传导可 保护免受过量自由基的破坏性影响。因此，我们假设， 西方饮食引起的H2S产生是ED发展的关键因素。在本建议中，我们 旨在通过检测酶的水平来了解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 调节抗氧化能力。我们还旨在了解H2S作用与 亚硝基化影响蛋白激酶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H2S产生的转基因小鼠模型 亚硝基化和改变的蛋白激酶G信号传导。小鼠将接触西方饮食和口服疗法 以提高H2S的产生将被研究作为治疗ED的潜在疗法。

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.