S-MARS

火星火星

• 批准号: 7720627
• 负责人: REBECCA DIN-DZIETHAM
• 金额: $ 9.76万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720627
• 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; 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; 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; 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).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中央赠款提供的资源 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，在列出的机构中可能会被压制 对于中心，这不一定是调查员的工厂。 在早期，血管疾病，大动脉功能，成人和评估的血管基因表达异常的主要目标是相关性，并且潜在的病原体介导途径在血管功能障碍和血管基因之间的潜在病原体介导途径。生物学因素因肥胖而易于肥胖，共同的，同时发生的疾病可能反映了复杂的相互作用生物学因素和社会心理和文化环境。 综上所述，这项研究将是将人类血管mRNA的变化与va scular功能和肥胖的总体上联系起来，预计将对分子基本ESS的新见解以及高风险的非洲美国肥胖受试者的ento虫功能障碍。 具体目的是： 1。确定脉管变化的基因表达是否是在存在脉络性僵硬症的情况下，在存在血管性基因表达的情况下，在存在的血管功能分布的情况下，是否是圆锥形的基因表达个人。将诱导血管mRNA表达的变化血管重塑和血管刚度。 信号通路，2）洞察力的洞察力。 2。确定胰岛素抗性和炎症是否会介导或模块化。血管功能障碍和个体中观察到的基因表达失衡。 3。评估钠摄入操纵对血管功能和基因表达的影响：修复，更大的动脉僵硬和血管疗法的失衡：脉管保护基因表达有利于前者，而低钠饮食将是BP的结果。减少基因表达的不平衡在肥胖者中会更大。 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 +横截面阶段将招募110名居住在亚特兰大地区的成年美国人，由Body-Ma SS-Index（BMI）分层：LEAN（BMI 25 kg/m2）和肥胖（BMI E30 kg/m2）性别比率将为1：1。根据肥胖中血管功能障碍障碍的文献，该样本量是钙化的。 +在募集的结尾，每个组将根据血管功能的四分之一分布进行分类。 。肥胖症，即动脉最僵硬的肥胖症（边界p = 0.07）。研究。由于我们的血管基因带有血管功能障碍，因此，支撑的设计是最多的应用过程，我们将邀请HABE参与Theel的CRC数据库。在研究人群部分中）。 12虽然高血压的风险与主动脉僵硬有关的第一事件和器官损害的第一事件似乎是为冠状动脉分级的，1 6中风，16,17和肾功能障碍。13,18 +与钠摄入量进行的跨越随机试验与最后一步。 ）。