Diversity Supplement to Role of Testosterone Induction of Hydrogen Sulfide in Erectile Dysfunction

硫化氢睾酮诱导勃起功能障碍作用的多样性补充

• 批准号: 10605389
• 负责人: Justin David LaFavor
• 金额: $ 11.27万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605389
• 关键词: Affect; Agonist; American; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Arteries; Binding; Biological Assay; Blood Vessels; Career Choice; Castration; Cell Nucleus; Chronic; Clinical Trials; Contracts; Cystathionine; Dependence; Diabetes Mellitus; Distal; Dose; Effectiveness; Electric Stimulation; Endothelium; Enzymes; Erectile dysfunction; Fellowship; Fostering; Fractionation; Free Radicals; Gene Chips; Genes; Genetic Transcription; Health; Health Care Costs; Hydrogen Sulfide; Hypertension; Hypogonadism; Incubated; Injection of therapeutic agent; Intervention; Lyase; Maintenance; Measurement; Measures; Mediating; Mentored Research Scientist Development Award; Metabolic syndrome; Microdialysis; Modeling; Mus; Muscle; Muscle function; Nerve; Nuclear; Obesity; Operative Surgical Procedures; Oral; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Patients; Penile Prosthesis; Physiological; Prevalence; Prodrugs; Production; Property; Prostate Cancer therapy; Proteins; Reactive Oxygen Species; Research; Research Personnel; Research Training; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Secondary to; Serum; Signal Transduction; Signaling Molecule; Smooth Muscle; Structure of internal iliac artery; Subgroup; Sulfhydryl Compounds; Symptoms; System; Techniques; Testing; Testosterone; Tissues; Treatment Cost; United States; Urology; Vascular blood supply; Vasodilation; Western Blotting; Wild Type Mouse; Work; cardiometabolism; career development; common symptom; cost; design; diet-induced obesity; electric field; in vivo; inhibitor; male; men; mouse model; neurovascular; parent grant; penis; phosphoric diester hydrolase; pressure; protective effect; response; restoration; sham surgery; sulfhydration; transcription factor; trend; western diet

R03 Project Summary/Abstract Testosterone insufficiency is an adverse health condition that affects an increasing number of men. It may be caused by prostate cancer treatment, but also by conditions associated with poor cardiometabolic health such as obesity, diabetes, and hypertension. Erectile dysfunction (ED) is a common symptom in men with testosterone insufficiency. The proposed research seeks to identify why testosterone has a protective effect on the erectile system. Specifically, the possibility that testosterone activates cystathionine γ-lyase (CSE) will be investigated. CSE is the primary enzyme that produces hydrogen sulfide in the vasculature. Hydrogen sulfide is an important cellular signaling molecule that is known to have antioxidant, anti-inflammatory, and vasodilatory properties. The vasodilatory effects of testosterone will be investigated in genetically modified mice lacking the CSE gene, as well as their unmodified littermate controls. Tissue segments from these animals will also be incubated with varying concentrations of testosterone, after which hydrogen sulfide production capacity will be measured. Tissue segments from the corpus cavernosum and the arteries responsible for supplying blood to the penis will be used for these studies, which include the internal iliac artery and proximal and distal segments of the internal pudendal artery. Previous studies indicate that chronic oxidative stress is a causative factor in ED pathogenesis in response to testosterone insufficiency. One mechanism by which hydrogen sulfide exerts cellular signaling is through binding to protein thiol groups, termed sulfhydration. It is hypothesized that hydrogen sulfide acts in such a manner to promote the nuclear related factor 2 (Nrf2) translocation to the nucleus. Nrf2 is an important transcription factor that regulates transcription of many cytoprotective and antioxidant genes. The ability of hydrogen sulfide to induce antioxidant defense and alleviate erectile dysfunction in a mouse model of testosterone insufficiency will be investigated. Male mice will receive a sham or castration surgery, after which castrated mice will remain untreated, or receive a low-dose or a high-dose of an orally active, slow-releasing hydrogen sulfide donor. Following the intervention, erectile function will be assessed by measuring intracavernous pressure changes in response to electrical stimulation of the cavernous nerve. Neurovascular, endothelial, and smooth muscle function will be assessed in the corpus cavernosum, internal iliac artery, and distal and proximal segments of the internal pudendal artery using an ex vivo myograph system. Expression of cytoprotective and antioxidant genes regulated by Nrf2 will be assessed in these tissues by quantitative RT- PCR. Cytosolic and nuclear content of Nrf2 in these tissues will be measured by cellular fractionation and Western blot. The penile redox state will be examined by measuring in vivo reactive oxygen species using a microdialysis technique.

R03 项目总结/摘要 睾酮不足是一种影响越来越多男性的不良健康状况。它 可能是由前列腺癌治疗引起的，但也可能是由与心脏代谢不良相关的疾病引起的 肥胖、糖尿病、高血压等健康问题。勃起功能障碍（ED）是男性的常见症状 睾丸激素不足。拟议的研究旨在确定为什么睾酮具有保护作用 对勃起系统的影响。具体来说，睾酮激活胱硫醚γ-裂解酶（CSE）的可能性 将被调查。 CSE 是在脉管系统中产生硫化氢的主要酶。氢 硫化物是一种重要的细胞信号分子，具有抗氧化、抗炎等作用 血管舒张特性。睾酮的血管舒张作用将在转基因中进行研究 缺乏 CSE 基因的小鼠及其未经修饰的同窝对照小鼠。来自这些的组织片段 动物还将与不同浓度的睾酮一起孵育，然后硫化氢 将测量生产能力。海绵体和动脉的组织片段 负责向阴茎供血的血管将用于这些研究，其中包括髂内动脉 以及阴部内动脉的近端和远端段。 既往研究表明，慢性氧化应激是 ED 发病机制的一个致病因素。 对睾酮不足的反应。硫化氢发挥细胞信号传导的一种机制是 通过与蛋白质硫醇基团结合，称为硫酸化。据推测，硫化氢的作用是 这种方式促进核相关因子2（Nrf2）易位至细胞核。 Nrf2是一个重要的 调节许多细胞保护和抗氧化基因转录的转录因子。的能力 硫化氢在小鼠模型中诱导抗氧化防御并减轻勃起功能障碍 将调查睾酮不足。雄性小鼠将接受假手术或去势手术，之后 阉割的小鼠将不接受治疗，或接受低剂量或高剂量的口服活性缓释药物 硫化氢供体。干预后，将通过测量来评估勃起功能 海绵体内压力因海绵体神经的电刺激而变化。神经血管， 将评估海绵体、髂内动脉和平滑肌的内皮和平滑肌功能 使用离体肌动描记器系统观察阴部内动脉的远端和近端部分。表达 将通过定量 RT- 评估这些组织中受 Nrf2 调节的细胞保护和抗氧化基因 PCR。这些组织中 Nrf2 的胞浆和核含量将通过细胞分级和 蛋白质印迹。将通过使用测量体内活性氧来检查阴茎氧化还原状态 微透析技术。