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

基本信息

批准号：
10735008
负责人：
Justin David LaFavor
金额：
$ 6.16万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10735008
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

项目摘要

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.

项目概要/摘要睾酮不足是一种影响越来越多男性的不良健康状况。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、糖尿病和高血压等健康问题是男性的常见症状。拟议的研究旨在确定睾酮具有保护作用的原因。具体来说，睾酮激活胱硫醚γ-裂解酶（CSE）的可能性。将研究 CSE 是在脉管系统中产生硫化氢的主要酶。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，以及这些小鼠未经修饰的同窝对照的组织片段。动物还将与不同浓度的睾酮一起孵育，然后硫化氢将测量海绵体和动脉的组织片段的生产能力。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。硫化氢发挥细胞信号传导的一种机制是对睾酮不足的反应。通过与蛋白质硫醇基团结合，称为硫化氢作用。这种方式对于促进核相关因子2(Nrf2)向细胞核的易位是一个重要的作用。转录因子具有调节许多细胞保护和抗氧化基因转录的能力。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研究睾酮不足的情况，然后对雄性小鼠进行假手术或去势手术。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干预后，将通过测量评估勃起功能。对海绵体神经的电刺激作出反应的海绵体内压力变化。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系统表达阴部内动脉的远端和近端部分。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。将通过细胞分级和测量来测量这些组织中 Nrf2 的细胞质和细胞核含量。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。