TNF-alpha: a key player in erectile (dys)function

肿瘤坏死因子-α：勃起(Dys)功能的关键角色。 6.项目摘要/摘要 目前和新兴的临床研究表明，阴茎血管床是一种敏感的指标 早期血管功能障碍，即ED是全身性血管疾病的早期临床表现， 对心血管事件有独立的风险。肿瘤坏死因子-α(TNF-α)，一种促肿瘤坏死因子-α。 炎性细胞因子是许多心血管疾病(高血压、糖尿病)的重要诱因 和代谢紊乱)。勃起功能障碍(ED)患者的肿瘤坏死因子水平也升高。 没有心血管疾病)，但到目前为止还没有研究表明肿瘤坏死因子对勃起(Dys)功能的作用。 该项目建议调查肿瘤坏死因子对勃起功能的影响以及肿瘤坏死因子如何导致 高血压相关的ED。更具体地说，我们将测试促炎症细胞因子的假设 肿瘤坏死因子-β增强海绵体平滑肌细胞的收缩反应，并在 高血压相关的ED。 提出了三个具体目标，所有目标都定义了肿瘤坏死因子-1的具体机制 增加海绵体收缩反应并导致勃起功能障碍： 具体目的1：验证肿瘤坏死因子增强海绵体收缩肌敏感性的假说 平滑肌细胞，导致勃起功能受损。 具体目标2：验证降低NO生物利用度和增强RhoA/Rho激酶的假说 信号转导为与升高的肿瘤坏死因子水平相关的勃起功能受损提供了机制。 具体目标3：验证肿瘤坏死因子在盐敏感型勃起功能障碍中起主要作用的假设 高血压和肿瘤坏死因子的作用部分是通过增加ET-1的表达来实现的。 拟议的研究，整合了生理学、药理学、生化、分子和细胞 技术，将有助于更好地理解肿瘤坏死因子对阴茎功能的影响，以及 肿瘤坏死因子水平异常与勃起功能障碍相关的功能性血管改变。身份识别 ED和心血管血管中肿瘤坏死因子-β含量升高的原因及机制 疾病可以促进疾病的治疗。由于心血管疾病和勃起功能障碍是一种主要的公共卫生 全球面临的挑战，主要是由不断增加的肥胖和人口老龄化推动的，我们的 该提案非常符合美国国立卫生研究院的使命。

TNF-alpha: a key player in erectile (dys)function. 6. PROJECT SUMMARY/ABSTRACT Current and emerging clinical research studies suggest that the penile vascular bed is a sensitive indicator of early vascular dysfunction, i.e., ED is an early clinical manifestation of generalized vascular disease and carries an independent risk for cardiovascular events. Tumor necrosis factor-alpha (TNF-¿), a pro- inflammatory cytokine, is an important contributor to many cardiovascular diseases (hypertension, diabetes and metabolic disorders). TNF-¿ levels are also increased in patients with erectile dysfunction (ED) (with or without cardiovascular disease), but so far no study has addressed the role of TNF-¿ on erectile (dys)function. This project proposes to investigate the effects of TNF-¿ on erectile function and how TNF-¿ leads to hypertension-associated ED. More specifically, we will test the hypothesis that the pro-inflammatory cytokine TNF-¿ increases contractile responses of cavernosal smooth muscle cells and plays a direct role in hypertension-associated ED. Three specific aims are proposed, all providing a definition of the specific mechanisms by which TNF-¿ increases cavernosal contractile responses and leads to eretile dysfunction: Specific aim 1: To test the hypothesis that TNF-¿ enhances the constrictor sensitivity of cavernosal smooth muscle cells, leading to impaired erectile function. Specific aim 2: To test the hypothesis that decreased NO bioavailability and augmented RhoA/Rho kinase signaling provide mechanisms for impaired erectile function associated with increased TNF-¿ levels. Specific aim 3: To test the hypothesis that TNF-¿ plays a major role in ED associated with salt-sensitive hypertension and that TNF-¿ effects are partially mediated by increased ET-1 expression. The proposed studies, integrating physiological, pharmacological, biochemical, molecular and cellular techniques, will help to better understand the effects of TNF-¿ on penile function, as well as the contribution of abnormal TNF-¿ levels to functional vascular changes associated with erectile dysfunction. Identification of causal factors and mechanisms responsible for increased vascular content of TNF-¿ in ED and cardiovascular disease may advance disease treatment. Since cardiovascular diseases and ED are a major public health challenge worldwide and are being fueled mainly by increasing obesity and ageing of the population, our proposal is very much in accordance with the mission of the NIH.