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

描述(申请人提供)：目前和新兴的临床研究表明，阴茎血管床是早期血管功能障碍的敏感指标，即ED是全身性血管疾病的早期临床表现，并具有心血管事件的独立风险。肿瘤坏死因子-1是一种促炎细胞因子，是许多心血管疾病(高血压、糖尿病和代谢紊乱)的重要致病因子。在勃起功能障碍(ED)患者(有或无心血管疾病)中，肿瘤坏死因子-1的水平也会升高，但到目前为止还没有研究表明肿瘤坏死因子-1对勃起功能(DYS)的作用。本项目旨在研究肿瘤坏死因子-1对勃起功能的影响，以及肿瘤坏死因子-1如何导致高血压相关的勃起功能障碍。更具体地说，我们将测试促炎细胞因子TNF-1增加海绵体平滑肌细胞的收缩反应，并在高血压相关的ED中发挥直接作用的假设。提出了三个特定的目标，都为肿瘤坏死因子-1增加海绵体收缩反应和导致勃起功能障碍的具体机制提供了定义：特定目标1：检验假设：肿瘤坏死因子-1增强海绵体平滑肌细胞的收缩敏感性，导致勃起功能受损。具体目的2：验证NO生物利用度降低和RhoA/Rho激酶信号增强为勃起功能受损提供与肿瘤坏死因子-1水平升高相关的机制的假说。具体目的3：验证一种假说，即肿瘤坏死因子-1在盐敏感型高血压相关的勃起功能障碍中起主要作用，并且肿瘤坏死因子-1的作用部分是通过增加ET-1表达来实现的。这些研究将结合生理学、药理学、生化、分子和细胞学技术，将有助于更好地了解肿瘤坏死因子-1对阴茎功能的影响，以及异常的肿瘤坏死因子-1水平在勃起功能障碍相关的功能性血管改变中的作用。明确ED和心血管疾病中血管中肿瘤坏死因子-1含量升高的原因和机制可能会促进疾病的治疗。由于心血管疾病和勃起功能障碍是全球范围内的重大公共卫生挑战，而且主要是由人口日益肥胖和老龄化造成的，我们的建议非常符合美国国立卫生研究院的使命。与公共卫生相关：美国有3000万男性患有勃起功能障碍，预计到2025年这一数字将翻一番。ED被认为是一个重大的公共卫生问题，严重影响患者及其伴侣的生活质量，随着年龄的增长，ED变得越来越普遍。此外，由于许多相同的原因，数量不详的女性也患有性功能障碍。勃起功能障碍的治疗有多种选择，包括真空治疗、海绵体内和经尿道药物治疗、手术治疗以及最近开发的口服药物。不幸的是，尽管有这些选择，ED在许多患者中仍然存在。西地那非和其他PDE-5抑制剂在治疗多种形式的ED方面都取得了成功，但患者往往无法从这些药物的使用中受益。此外，心血管疾病患者经常接受硝酸盐治疗，这排除了PDE-5抑制剂的使用。这项建议中概述的研究旨在确定肿瘤坏死因子-α，一种促炎细胞因子，其水平在心血管疾病和ED患者的血浆中升高，如何改变海绵体反应性并导致ED。了解由细胞因子激活的信号通路的组成以及它们是如何联系在一起的，对于全面理解导致ED的机制是必要的。因此，这项工作将大大有助于更好地了解勃起疾病的机制，以及确定新的和更有效的治疗方案来恢复勃起功能。

DESCRIPTION (provided by applicant): 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-1), a pro- inflammatory cytokine, is an important contributor to many cardiovascular diseases (hypertension, diabetes and metabolic disorders). TNF-1 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-1 on erectile (dys)function. This project proposes to investigate the effects of TNF-1 on erectile function and how TNF-1 leads to hypertension-associated ED. More specifically, we will test the hypothesis that the pro-inflammatory cytokine TNF-1 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-1 increases cavernosal contractile responses and leads to eretile dysfunction: Specific aim 1: To test the hypothesis that TNF-1 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-1 levels. Specific aim 3: To test the hypothesis that TNF-1 plays a major role in ED associated with salt-sensitive hypertension and that TNF-1 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-1 on penile function, as well as the contribution of abnormal TNF-1 levels to functional vascular changes associated with erectile dysfunction. Identification of causal factors and mechanisms responsible for increased vascular content of TNF-1 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. PUBLIC HEALTH RELEVANCE: Thirty million men in the United States suffer from ED and this number is expected to double by 2025. Considered a major public health problem, which seriously affects the quality of life of patients and their partners, ED becomes increasingly prevalent with age. In addition, an undetermined number of women also suffer from sexual dysfunction based on many of the same etiologies. A wide variety of therapeutic options are available for the treatment of ED, including vacuum therapy, intracavernous and transurethral drug therapy, surgery, and recently developed oral medications. Unfortunately, despite these options, ED persists in many patients. Sildenafil and other PDE-5 inhibitors have been successful in the treatment of many forms of ED, but often, patients fail to benefit from use of these agents. Furthermore, patients with cardiovascular disease very often are under nitrate therapy, which precludes the use of PDE-5 inhibitors. The studies outlined in this proposal aim to determine how TNF-alpha, a pro-inflammatory cytokine whose levels are elevated in plasma from patients with cardiovascular diseases and ED, changes cavernosal reactivity and leads to ED. Understanding the components of the signaling pathways activated by cytokines and how they link together is necessary for a complete comprehension of the mechanisms leading to ED. Thus, this work will greatly assist in a better understanding of mechanisms of erectile disease, as well as in the identification of novel and more efficacious therapeutic options for restoration of erectile function.