S-MARS

火星火星

• 批准号: 7960775
• 负责人: REBECCA DIN-DZIETHAM
• 金额: $ 0.33万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960775
• 关键词: Address; Adult; African American; Aldosterone; Angiotensin II; Area; Arteries; Biological Factors; Biological Markers; Biopsy; Blood Pressure; Blood Vessels; Body mass index; Candidate Disease Gene; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Coronary heart disease; Cross-Sectional Studies; Databases; Disease; Double-Blind Method; Enrollment; Environment; Epidemiologic Studies; Event; Functional disorder; Funding; Gender; Gene Expression; Genes; Genetic Crossing Over; Grant; Human; Hypertension; Individual; Inflammation; Institution; Insulin Resistance; Intake; Intervention; Kidney; Lead; Life; Link; Literature; Measurement; Mediating; Mediation; Minority; Modeling; Molecular; Molecular Profiling; Nitric Oxide; Obesity; Organ; Other Genetics; Oxidative Stress; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiological; Pilot Projects; Population Study; Process; Randomized Controlled Clinical Trials; Recruitment Activity; Relative (related person); Relative Risks; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Resistance; Resources; Risk; Sample Size; Series; Signal Pathway; Sodium; Sodium-Restricted Diet; Source; Speed; Staging; Stroke; Subgroup; Testing; United States National Institutes of Health; Vascular Diseases; Vascular remodeling; arterial stiffness; base; design; experience; feeding; high risk; insight; interest; mRNA Expression; normotensive; psychosocial; research study; stem

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major objective of this project is to characterize the abnormalities of vascular gene expression occurring in early, subclinical stages of vascular disease, as assessed by large artery function, in adult obesity and to assess its correlates and the potential pathobiological mediating pathways between vascular dysfunction and vascular gene expression. While compelling evidence indicates that genetic and other biological factors predispose to obesity and hypertension, these common, co-occurring disorders likely reflect a complex interplay between biological factors and the psychosocial and cultural environment. Taken together, this series of studies will be among the first to link changes in human vascular mRNA expression profiles with physiologic alterations in vascular function and obesity. Overall, it is anticipated that these experiments will provide new insights into the molecular basis of vascular stiffness and endothelial dysfunction in high-risk African-American obese subjects. The specific aims were: 1. To determine whether vasculopathic gene expression is up-regulated and vasculoprotective gene expression is down-regulated in presence of arterial stiffness, as defined by the upper quartile of the vascular function distribution. These abnormalities would thus create a deleterious imbalance of vasculopathic: vasculoprotective gene expression in subjects with vascular dysfunction relative to those without. Furthermore, we hypothesize that this imbalance will be greater in obese than in lean individuals. Our model predicts that activation of Angiotensin (Ang) II and aldosterone combined with decreased activity of nitric oxide (NO) and PPAR-¿ will induce changes in vascular mRNA expression that promote vascular remodeling and vascular stiffness. Although there are many candidate genes, we will focus on genes that: 1) characterize the activity of the Renin Angiotensin Aldosterone System (RAAS), nitric oxide (NO), and peroxisome proliferators-activated receptor (PPAR) ¿ signaling pathways, 2) influence vascular tone and 3) influence distensibility. Overall, it is anticipated that these experiments will provide new insights into the molecular basis of vascular stiffness and endothelial dysfunction in high-risk African-American obese subjects. 2. To determine whether insulin-resistance, oxidative stress, and inflammation mediate or modulate the association of interest. In case of mediation, the effect of obesity on vascular function and vascular gene expression will be explained away partially or totally by these biomarkers. In case of modulation, the presence of these factors will markedly increase the vascular dysfunction and the gene expression imbalance observed in obese individuals. 3. To assess the effect of sodium intake manipulation on vascular function and gene expression: (a) high intake of sodium will lead to increased blood pressure, greater arterial stiffness, and imbalance of the vasculopathic:vasculoprotective gene expression in favor of the former, whereas low sodium diet will lead to the opposite effect and the net result will be a BP reduction; (b) the high-low gradient in vascular dysfunction and imbalance of gene expression will be greater in obese than in lean people. To address this aim, the original design was as follows: The design for the proposed 3-year study is a cross-sectional study followed by a cross-over, two-period, double-blind randomized trial. + The cross-sectional stage will recruit 110 adult African Americans residing in the Atlanta area stratified by anthropometric status as defined by body-mass-index (BMI): Lean (BMI 25 kg/m2) and obese (BMI e30 kg/m2). Within each stratum, the gender ratio will be 1:1. This sample size was calculated based on the literature of vascular dysfunction in obese. + At the end of the recruitment, each group will be categorized based on the quartile distribution of vascular function. Obese in the fourth quartile of vascular function and lean in the first quartile will undergo gluteal biopsy. The rationale for choosing this design stems from our experience in the pilot study. Despite the large difference in BMI between the obese and lean enrolled in the pilot study (37.3 ¿ 1.5 kg/m2 vs. 22.2 ¿ 1.5 kg/m2, p0.0001), the overall distribution of vascular function for obese was not quite different from that of lean, though those in the highest quartile for systemic resistance, and the lowest quartile for arterial compliance, i.e., those with stiffest arteries, were obese (borderline p=0.07). Another reason why we did not observe any difference in vascular function between obese and lean may be the small sample size (total n=14) or the relatively healthy status of the obese enrolled in the study. Because we are interested in vascular gene expression associated with vascular dysfunction, the proposed design is the most appropriate. To speed up the recruitment process we will invite the people in the CRC database who have enrolled in the endothelial function study and those who are through with the vascular function study (see details in study population section). The reason why gluteal biopsy is performed on the selected quartiles is because epidemiological studies show that the relative risk of developing hypertension for normotensive people is statistically significantly greater for those in the 4th quartile of the distribution of arterial stiffness compared to those in the first quartile,12 whereas the risk for hypertensives to develop an end-organ-damage first event in relation to aortic stiffness appears to be graded for coronary heart disease,16 stroke,16,17 and renal dysfunction.13,18 + Cross-over randomized trial with sodium intake manipulation will be the last step. It encompasses feeding and free-living components. Because gluteal biopsy is not a simple test, we opted to minimize the risk of misclassification attached to sodium intake and measurement by conducting controlled fed interventions in the subgroup with biopsy (n ~ 30).

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 该项目的一个主要目的是表征在早期的血管疾病亚临床阶段发生的血管基因表达的异常，如大动脉功能，成人肥胖症所评估，并评估其相关性及其潜在病原体介导途径之间的潜在病原体介导途径。尽管令人信服的证据表明，遗传和其他生物学因素易于肥胖和高血压，但这些常见的，共发生的疾病可能反映了生物学因素与社会心理和文化环境之间的复杂相互作用。 综上所述，这一系列的研究将是第一个将人血管mRNA表达谱变化与血管功能和肥胖症的物理改变联系起来的研究之一。总体而言，预计这些实验将为非裔美国肥胖受试者中血管僵硬和内皮功能障碍的分子基础提供新的见解。 具体目的是： 1。为了确定血管性基因表达是否上调，并且在存在动脉刚度的情况下，血管保护基因表达被下调，如血管功能分布的上四分位数所定义。因此，这些异常将造成血管性疾病的缺失失衡：血管保护基因表达在具有血管功能障碍的受试者相对于没有血管功能障碍的受试者。此外，我们假设这种失衡在肥胖者中会更大。我们的模型预测激活血管紧张素（ANG）II和醛固酮与一氧化氮（NO）和PPAR-的活性降低将诱导血管mRNA表达的变化，从而促进血管重塑和血管僵硬。尽管有许多候选基因，但我们将重点关注：1）表征肾素血管紧张素醛固酮系统（RAAS），一氧化氮（NO）和过氧化物增殖物激活受体（PPAR）»信号途径，2）影响血管张力和3）影响血管张力和3）影响血管张开。总体而言，预计这些实验将为非裔美国肥胖受试者中血管僵硬和内皮功能障碍的分子基础提供新的见解。 2。确定胰岛素抵抗，氧化应激和炎症是否介导或调节目标关联。如果进行调解，这些生物标志物将部分或完全解释肥胖对血管功能和血管基因表达的影响。在调节的情况下，这些因素的存在将显着增加肥胖个体中观察到的血管功能障碍和基因表达失衡。 3。评估钠摄入操纵对血管功能和基因表达的影响：（a）钠的高摄入量将导致血压升高，动脉僵硬更大以及血管疾病的失衡：血管果保护基因表达对前者的有利，而低钠饮食将导致相反的钠饮食和相反的效果和净效果。 （b）血管功能障碍和基因表达不平衡的高低梯度在肥胖者中会更大。 为了解决这个目标，原始设计如下： 拟议的三年研究的设计是一项横断面研究，然后进行了横断面，两周的双盲随机试验。 +横截面阶段将招募110名居住在亚特兰大地区的非裔美国人，该非人体测量状态分层，该状态由人体质量索引（BMI）定义：LEAN（BMI 25 kg/m2）和肥胖（BMI E30 kg/m2）。在每个层中，性别比率将为1：1。该样本量是根据肥胖中血管功能障碍的文献计算的。 +在招募结束时，每个组将根据血管功能的四分位数分布进行分类。肥胖是血管功能的第四四分之一，在第一个四分位数中瘦会进行臀肌活检。从我们在试点研究中的经验中选择此设计步骤的理由。尽管进行了试点研究的肥胖和瘦肉之间的BMI差异很大（37.3€1.5 kg/m2 vs. 22.2 vs. 1.5 kg/m2，p0.0001），肥胖的血管功能的总体分布与瘦弱的肥胖相差并没有完全不同，尽管那些在最高四重奏中均与最高量的高级抗衡。肥胖（边界p = 0.07）。我们没有观察到肥胖和瘦肉之间血管功能有任何差异的另一个原因可能是样本量（总n = 14）或研究中肥胖的相对健康状况。由于我们对与血管功能障碍相关的血管基因表达感兴趣，因此提出的设计是最合适的。为了加快招聘过程，我们将邀请参加内皮功能研究的CRC数据库中的人们以及通过血管功能研究的人（请参阅研究人群部分中的详细信息）。在选定的四分位数上进行肠麸活检的原因是因为流行病学研究表明，正常潮湿的人在统计上的相对风险在统计学上的相对风险显着更大，而动脉僵硬分布的第四四分位四分位数则比第一个四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位四分位数，而与第一个四分光性相比，对高血压的风险逐渐成分，而迫切需要迫使高级疗法的稳固性，而僵硬的型号则是相互依恋的事件。疾病，16个中风，16,17和肾功能障碍。13,18 +通过钠摄入操纵进行的跨界随机试验将是最后一步。它包括喂食和自由活动的组件。由于臀肌活检不是一个简单的测试，因此我们选择最大程度地降低钠摄入量错误的风险，并通过对活检中的子组进行受控干预（n〜30）来进行测量。