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

项目摘要/摘要 这项建议旨在为申请者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量学和运动科学的博士培训，并已获得 在亚瑟·伯内特博士的指导下进行的泌尿外科博士后培训，亚瑟·伯内特博士是基础泌尿外科领域公认的领导者 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，他是一名国际 在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。这个 拟议的培训计划将继续完善PI的科学、技术和专业技能 并帮助他过渡到独立。PI将利用广泛的培训和专业 约翰霍普金斯医学院的发展资源。 这项拟议的研究旨在确定硫化氢(H2S)作为一种调节剂的潜在作用 勃起功能。我们之前已经建立了西方饮食诱导的勃起功能障碍的啮齿动物模型 (编辑)。初步研究表明，过量的蛋白质亚硝化(一氧化氮(NO)与蛋白质的结合 硫醇)对西方饮食的反应加速了勃起功能障碍的发展。西式饮食也会减少 在勃起组织中产生硫化氢(H2S)。我们的研究团队此前已经证明， 硫化氢通过蛋白质硫水化(硫化氢与硫醇结合)施加细胞信号，这通常与 亚硝化的影响。利用一种新开发的技术在体内测量活性氧物种 表明西方饮食增加了阴茎自由基的产生，而这一过程会被亚硝化作用加速。 此前已有报道称，硫化氢具有抗氧化性能，通过硫水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，我们假设减少了 西方饮食产生的硫化氢是ED发生的关键因素。在这项提案中，我们 旨在通过检测酶的水平来了解硫化氢如何影响阴茎的氧化还原状态 产生硫化氢，测量阴茎自由基，并研究硫酸盐水合信号通路 调节抗氧化能力。我们还致力于了解硫化氢作用和 亚硝酸化影响蛋白激酶G信号和勃起功能。为了实现这些目标，我们将使用 转基因小鼠模型的硫化氢产量减少，硫化氢产量增加，过量 亚硝化，并改变蛋白激酶G信号。小鼠将接触到西方饮食和口服疗法 增加硫化氢的产生将被作为治疗ED的潜在疗法进行研究。

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.