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).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的一个主要目标是通过大动脉功能评估成人肥胖症患者在血管疾病早期、亚临床阶段发生的血管基因表达异常的特征，并评估其相关性以及血管功能障碍和血管基因表达之间的潜在病理生物学介导途径。 虽然令人信服的证据表明遗传和其他生物因素容易导致肥胖和高血压，但这些常见的、同时发生的疾病可能反映了生物因素与社会心理和文化环境之间复杂的相互作用。 总而言之，这一系列研究将是首批将人类血管 mRNA 表达谱的变化与血管功能和肥胖的生理变化联系起来的研究之一。总体而言，预计这些实验将为高风险非裔美国肥胖受试者血管僵硬度和内皮功能障碍的分子基础提供新的见解。 具体目标是： 1. 确定在存在动脉僵硬（由血管功能分布的上四分位数定义）的情况下，血管病变基因表达是否上调，而血管保护基因表达是否下调。因此，这些异常会在患有血管功能障碍的受试者中相对于没有血管功能障碍的受试者造成血管病：血管保护基因表达的有害不平衡。此外，我们假设肥胖者的这种不平衡会比瘦人更大。我们的模型预测，血管紧张素 (Ang) II 和醛固酮的激活加上一氧化氮 (NO) 和 PPAR-¿ 活性的降低将诱导血管 mRNA 表达的变化，从而促进血管重塑和血管僵化。尽管候选基因有很多，但我们将重点关注以下基因：1) 表征肾素血管紧张素醛固酮系统 (RAAS)、一氧化氮 (NO) 和过氧化物酶体增殖物激活受体 (PPAR) 信号通路的活性，2) 影响血管张力，3) 影响扩张性。总体而言，预计这些实验将为高风险非裔美国肥胖受试者血管僵硬度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相关关联。在中介的情况下，肥胖对血管功能和血管基因表达的影响将部分或完全由这些生物标志物解释。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. 评估控制钠摄入量对血管功能和基因表达的影响：（a）高钠摄入量会导致血压升高、动脉僵硬度增大以及血管病变：血管保护基因表达失衡，有利于前者，而低钠饮食会导致相反的效果，最终结果是血压降低； (b) 肥胖者的血管功能障碍和基因表达失衡的高低梯度比瘦人更大。 为了实现这一目标，最初的设计如下： 拟议的三年研究设计是一项横断面研究，随后进行交叉、两期、双盲随机试验。 + 横断面阶段将招募 110 名居住在亚特兰大地区的成年非裔美国人，根据身体质量指数 (BMI) 定义的人体测量状况进行分层：瘦 (BMI 25 kg/m2) 和肥胖 (BMI e30 kg/m2)。每个阶层内的性别比例为1:1。 该样本量是根据肥胖者血管功能障碍的文献计算的。 + 在招募结束时，将根据血管功能的四分位数分布对每组进行分类。血管功能第四个四分位的肥胖者和第一四分位的瘦者将接受臀肌活检。选择这种设计的理由源于我们的试点研究经验。尽管参加试点研究的肥胖者和瘦者之间的 BMI 存在很大差异（37.3 ¿ 1.5 kg/m2 与 22.2 ¿ 1.5 kg/m2，p0.0001），但肥胖者的血管功能总体分布与瘦者并没有太大差异，尽管那些处于全身阻力最高四分位数和动脉顺应性最低四分位数的人，即那些动脉最僵硬的人， 肥胖（边界 p=0.07）。我们没有观察到肥胖者和瘦者之间血管功能存在任何差异的另一个原因可能是样本量较小（总数=14）或参加研究的肥胖者的相对健康状况。因为我们对与血管功能障碍相关的血管基因表达感兴趣，所以所提出的设计是最合适的。为了加快招募过程，我们将邀请 CRC 数据库中已登记参加内皮功能研究的人员和已完成血管功能研究的人员（详细信息请参阅研究人群部分）。之所以在选定的四分位数上进行臀肌活检，是因为流行病学研究表明，血压正常的人患高血压的相对风险在统计学上显着高于动脉僵硬度分布的第四个四分位数的人，12 而高血压患者发生与主动脉僵硬度相关的终末器官损伤第一事件的风险似乎是根据冠心病进行分级的。 疾病、16 中风、16,17 和肾功能不全。13,18 + 控制钠摄入量的交叉随机试验将是最后一步。它包括进食和自由生活的部分。由于臀肌活检不是一项简单的测试，因此我们选择通过在活检亚组 (n ~ 30) 中进行受控喂养干预，尽量减少钠摄入量和测量错误分类的风险。