Role of Testosterone Induction of Hydrogen Sulfide in Erectile Dysfunction

硫化氢睾酮诱导在勃起功能障碍中的作用

• 批准号: 10549752
• 负责人: Justin David LaFavor
• 金额: $ 10.95万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549752
• 关键词: Affect; Agonist; American; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Anxiety; Aorta; Arteries; Binding; Biological Assay; Blood Vessels; Castration; Cell Nucleus; Chronic; Clinical Trials; Contracts; Cysteine Desulfhydrase; Cytoprotection; Dependence; Diabetes Mellitus; Distal; Distress; Dose; Effectiveness; Electric Stimulation; Endothelium; Enzymes; Erectile dysfunction; Fractionation; Free Radicals; Gene Chips; Genes; Genetic Transcription; Health; Health Care Costs; Hydrogen Sulfide; Hypertension; Hypogonadism; Incubated; Injection of therapeutic agent; Intervention; Life; Lyase; Maintenance; Measurement; Measures; Mediating; Mental Depression; 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; Quality of life; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Research; Research Personnel; Role; 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; Urethra; Vascular blood supply; Vasodilation; Western Blotting; Wild Type Mouse; Work; cardiometabolism; common symptom; cost; diet-induced obesity; electric field; in vivo; inhibitor; male; men; meter; mouse model; neurovascular; novel therapeutic intervention; penis; phosphoric diester hydrolase; pressure; protective effect; response; restoration; satisfaction; sham surgery; sulfhydration; transcription factor; trend; western diet

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.

项目摘要/摘要 睾丸激素不足是一种不良健康状况，会影响越来越多的男性。 可能是由前列腺癌治疗引起的，但也是由较差的心脏代谢的条件引起的 肥胖，糖尿病和高血压等健康状况。勃起功能障碍（ED）是男性的常见症状 睾丸激素不足。拟议的研究试图确定睾丸激素为何受到保护 对勃起系统的影响。具体而言，睾丸激素激活Cystathioninγ-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，已知具有抗氧化剂，抗炎和 血管舒张特性。将在一般修改中研究睾丸激素的血管舒张作用 缺乏CSE基因的小鼠及其未修饰的窝窝对照。这些组织段 动物还将与不同浓度的睾丸激素一起孵育，之后硫化氢 将测量生产能力。来自海绵体和动脉的组织段 负责向阴茎供应血液的研究将用于这些研究，其中包括内部动脉 以及内部底部动脉的近端和远端段。 先前的研究表明，慢性氧化应激是ED发病机理的基因制造者 对睾丸激素不足的反应。硫化氢执行细胞信号传导的一种机制是 通过与蛋白质硫醇基的结合，称为硫水。假设硫化氢在 这种方式促进核与核因子2（NRF2）转移到核us的方式。 NRF2很重要 调节许多细胞保护和抗氧化基因的转录的转录因子。能力 硫化氢可诱导抗氧化剂防御并减轻小鼠模型中的勃起功能障碍 将研究睾丸激素功能不全。雄性小鼠将接受假手术或cast割手术 cast割的小鼠将保持未经治疗，或者接受低剂量或高剂量的口服，缓慢释放 硫化氢供体。干预后，将通过测量来评估勃起功能 孔内压力响应着海绵神经的电刺激的响应。神经血管， 内皮和平滑肌功能将在海绵体，内部动脉内部和 使用离体肌电图系统的内部动脉的远端和近端段。表达 通过定量的RT-将评估由NRF2调节的细胞保护和抗氧化剂基因 pcr。 NRF2在这些组织中的胞质和核含量将通过细胞分馏和 蛋白质印迹。阴茎氧化还原状态将通过使用A的体内活性氧来检查 微透析技术。