Blood Pressure Control Determined by Chromosome 13

由 13 号染色体决定的血压控制

• 批准号: 7217708
• 负责人: Allen W Cowley
• 金额: $ 44.21万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217708
• 关键词: adrenal glands; angiotensin /renin /aldosterone hypertension; blood pressure; body fluid osmolarity; cardiovascular function; chromosomes; dietary sodium; electrolyte balance; endocrinology; functional /structural genomics; gender difference; gene expression; genetic models; genetic polymorphism; genetic regulation; genetic strain; genetic susceptibility; inbreeding; kidney function; laboratory rat; messenger RNA; microarray technology; molecular pathology; nutrition related tag

The goal of Project by Cowley is to use physiological and gene microarray expression data to determine how genes within four discrete regions of Chromosome 13 (Chr 13) initiate and/or maintain the cascade of events determining blood pressure salt-sensitivity and renal dysfunction in the Dahl S (SS) rat. As shown previously, introgression of the entire Chr 13 from the inbred Brown Norway (BN) strain of rat into the genomic background of the SS rat strain (consomic SS-13BN) substantially reduces salt-induced hypertension and proteinuria. We have now completed development of and have phenotyped 23 congenic inbred strains with overlapping BN Chr 13 chromosomal segments introgressed into SS. Four discrete congenic regions of these BN substitutions within the SS genomic background (congenic strains 1, 5, 9 and 26), that range in size from 4.5 to 16 Mbp resulted in significant protection from salt-induced hypertension in female rats. Reductions of the levels of hypertension ranged from 22 to 32 mmHg among these congenic strains. In addition, since sex differences affected the degree of protection from salt-induced hypertension in several of the .congenic strains, one of these strains (congenic strain 9) was selected to determine variations of genomic and physiological pathways that may explain these male and-female differences. We hypothesize that genes within these four congenic regions of Chr 13 collectively contribute to genome-wide responses and operate through shared functional pathways to improve the sodium excretory function of the kidney and thereby protect the organism from salt-induced hypertension. Three systems important in the regulation of sodium homeostasis and arterial pressure regulation will be assessed, the kidneys (cortex and medulla), the adrenals (reflecting autonomic and endocrine function) and the vasculature. Studies in Aim I will determine the sequential physiological changes in pathways under conditions of 0.4% salt diet and at 16 hr, 3 and 12 days after switching to a 4.0% salt diet. Aim 2 will utilize gene microarrays as a powerful assay system to identify pathways and networks that are linked to whole system physiology. Molecular profiles reflected by mRNA expression will be combined with physiological profiles obtained in Aim 1 in an integrative'analysis to identify the molecular patterns and pathways that underlie common physiological systems responsible for the phenotypic differences .between the SS rat and'the reduced salt-sensitivity of the congenic strains. >Even if little is currently known of the function of a differentially expressed gene, gene function can be reverse engineered by placing .them into the context of an overall functional pathway to predict gene-function relationships. The use of congenic strains within Chr 13 with well-defined blood pressure phenotypes provides a unique opportunity to produce an integrated picture of how genes within four discrete regions of Chr 13 modify salt-induced hypertension. This may provide valuable clues to define these critical pathways responsible for salt-induced forms of hypertension in human subjects, especially in high risk populations such as African-Americans.

Cowley项目的目标是使用生理和基因微阵列数据来确定基因如何 在13号染色体(Chr 13)的四个离散区域内，启动和/或维持一连串的事件 Dahl S(SS)大鼠血压、盐敏感性和肾功能损害的测定。如前所述， 近交系棕色挪威(BN)大鼠的整个Chr 13基因导入基因组背景 SS大鼠品系(联合SS-130亿)可显著降低盐诱导的高血压和蛋白尿。我们 现已完成23个BN重叠的同源自交系的开发和表型鉴定 CHR 13个染色体片段已整合到SS中。这些BN取代的四个离散的同源区 在SS基因组背景中(同源菌株1、5、9和26)，大小从4.5到16 MBP 对雌性大鼠盐源性高血压有明显的保护作用。减少的水平 在这些同源菌株中，高血压的范围从22到32毫米汞柱。另外，由于性别差异 影响了几个同源菌株对盐诱导高血压的保护程度，其中一个 选择这些菌株(同源菌株9)来确定基因组和生理途径的变异。 这可能解释了这些男性和女性的差异。我们假设这四个同源基因中的基因 CHR 13的区域共同参与全基因组的反应，并通过共享的功能 改善肾脏钠排泄功能从而保护机体免受盐诱导的途径 高血压。钠稳态和动脉压调节中的三个重要系统 将评估调节、肾脏(皮质和髓质)、肾上腺(反映自主神经和 内分泌功能)和血管系统。在AIM I中的研究将确定顺序的生理变化 在0.4%盐饮食条件下以及转换为4.0%盐饮食后16小时、3天和12天的路径中。 AIM 2将利用基因微阵列作为一个强大的测试系统来识别 与整个系统生理学相联系。由mRNA表达反映的分子图谱将与 在综合分析中在目标1中获得的生理图谱，以确定分子模式和 导致表型差异的共同生理系统的基础途径。 SS大鼠和同源菌株对盐的敏感性降低。即使目前对的功能知之甚少 一个差异表达的基因，基因功能可以通过将它们置于 预测基因-功能关系的整体功能途径。CHR 13中同源菌株的利用 明确的血压表型提供了一个独特的机会来产生一个完整的图像 Chr 13四个离散区域内的基因如何改变盐诱导的高血压。这可能会提供有价值的 确定这些导致人类受试者盐源性高血压的关键途径的线索， 尤其是在非洲裔美国人等高危人群中。