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

TNF-α：勃起（功能障碍）的关键因素

基本信息

批准号：
8298246
负责人：
R Clinton Webb
金额：
$ 34.58万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298246
关键词：
Address Affect Age Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Biochemical Biological Availability Blood Vessels Cardiovascular Diseases Cell Maintenance Chimeric Proteins Chronic Clinical Clinical Research Comprehension DOCA Diabetes Mellitus Disease Endothelin-1 Erectile dysfunction Etanercept Etiology Event Flaccid Muscle Tone Functional disorder Hypertension In Vitro Inflammatory Link Mediating Mediator of activation protein Metabolic Diseases Mission Molecular Mus Neurons Nitrates Nitric Oxide Nitric Oxide Synthase Type I Obesity Operative Surgical Procedures Oral Pathway interactions Patients Penile Erection Peptides Pharmaceutical Preparations Pharmacotherapy Physiological Plasma Play Population Process Public Health Quality of life Relaxation Research Rho-associated kinase Role Sexual Dysfunction Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Sodium Chloride TNF gene Techniques Testing Therapeutic Tissues Translations Tumor Necrosis Factor-alpha United States United States National Institutes of Health Vacuum Vascular Diseases Vascular Endothelium Vasodilation Woman Work advanced disease base cardiovascular risk factor cytokine design human NOS3 protein human TNF protein improved in vivo inflammatory marker inhibitor/antagonist innovation insight kinase inhibitor knockout animal men neurotransmission novel novel therapeutic intervention protein expression research study response restoration salt sensitive sildenafil tool vascular bed

项目摘要

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.

TNF-α：勃起（功能障碍）的关键参与者。 6. 项目概要/摘要当前和新兴的临床研究表明，阴茎血管床是一个敏感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，具有心血管事件的独立风险。肿瘤坏死因子-α (TNF-¿) 炎症细胞因子，是许多心血管疾病（高血压、糖尿病和代谢紊乱）。勃起功能障碍 (ED) 患者的 TNF-¿ 水平也会升高（患有或没有心血管疾病），但迄今为止还没有研究探讨 TNF-¿ 对勃起（功能障碍）的作用。该项目旨在研究 TNF-¿ 对勃起功能的影响以及 TNF-¿ 如何导致高血压相关的 ED。更具体地说，我们将检验促炎细胞因子的假设 TNF-¿ 增加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，所有目标都提供了 TNF-¿ 增加海绵体收缩反应并导致勃起功能障碍：具体目标 1：检验 TNF-¿ 增强海绵体收缩器敏感性的假设平滑肌细胞，导致勃起功能受损。具体目标 2：检验降低 NO 生物利用度和增强 RhoA/Rho 激酶的假设信号传导提供了与 TNF-¿ 水平升高相关的勃起功能受损的机制。具体目标 3：检验 TNF-¿ 在与盐敏感相关的 ED 中起主要作用的假设高血压和 TNF-¿ 效应部分是由 ET-1 表达增加介导的。所提出的研究，综合了生理学、药理学、生化、分子和细胞技术，将有助于更好地了解 TNF-¿ 对阴茎功能的影响，以及异常的 TNF-¿ 水平会导致与勃起功能障碍相关的功能性血管变化。鉴定 ED 和心血管疾病中 TNF-¿ 血管含量增加的原因和机制疾病可能会促进疾病治疗。由于心血管疾病和 ED 是重大公共卫生问题世界范围内面临的挑战，主要是由于肥胖和人口老龄化的加剧，我们该提案非常符合 NIH 的使命。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased cavernosal relaxation by Phoneutria nigriventer toxin, PnTx2-6, via activation at NO/cGMP signaling.

DOI：
10.1038/ijir.2011.47
发表时间：
2012-03
期刊：
INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH
影响因子：
2.6
作者：
Nunes, K. P.;Wynne, B. M.;Cordeiro, M. N.;Borges, M. H.;Richardson, M.;Leite, R.;DeLima, M. E.;Webb, R. C.
通讯作者：
Webb, R. C.

Mitochondrial N-formyl peptides cause airway contraction and lung neutrophil infiltration via formyl peptide receptor activation.

DOI：
10.1016/j.pupt.2016.02.005
发表时间：
2016-04
期刊：
PULMONARY PHARMACOLOGY & THERAPEUTICS
影响因子：
3.2
作者：
Wenceslau, Camilla Ferreira;Szasz, Theodora;McCarthy, Cameron G.;Baban, Babak;NeSmith, Elizabeth;Webb, R. Clinton
通讯作者：
Webb, R. Clinton

Mitochondrial-derived N-formyl peptides: novel links between trauma, vascular collapse and sepsis.

DOI：
10.1016/j.mehy.2013.06.026
发表时间：
2013-10
期刊：
MEDICAL HYPOTHESES
影响因子：
4.7
作者：
Wenceslau, C. F.;McCarthy, C. G.;Goulopoulou, S.;Szasz, T.;NeSmith, E. G.;Webb, R. C.
通讯作者：
Webb, R. C.

Lipoxin A4 mediates aortic contraction via RHOA/RHO kinase, endothelial dysfunction and reactive oxygen species.