• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Narrowing Genetic Regions on Rat Chromosome Twelve Involved in the Development of Hypertension and Kidney Disease.
【24h】

Narrowing Genetic Regions on Rat Chromosome Twelve Involved in the Development of Hypertension and Kidney Disease.

机译：十二指肠上狭窄的遗传区域涉及高血压和肾脏疾病的发展。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hypertension is a disease which afflicts a third of U.S. adults over the age of 20, and 90-95% of the adult hypertensive cases are characterized as primary or essential hypertension, meaning that the underlying cause of the elevations in blood pressure are unknown. In addition, hypertension is one of the leading risk factors for chronic kidney disease, which affects 16.8% of adults over the age of 20 in the U.S. Unfortunately, substantial progress in the treatment and prevention of both hypertension and chronic kidney disease have not been made, partially due to their genetic complexity. Studies with inbred rat models, such as the SS (Dahl salt-sensitive) hypertensive and BN (Brown Norway) normotensive rat strains can help dissect the genetic complexity of hypertension and kidney disease. The SS strain develops hypertension and renal damage on elevated salt diets. Previous work has shown that a 6.1 Mb SS region on rat chromosome 12 significantly increases blood pressure and renal damage compared to the SSBN12 control rat strain, which was derived by transferring BN rat chromosome 12 onto the SS background.;This thesis examines the following hypotheses: (1) A gene(s) located between 13.41-19.55 Mb on rat chromosome 12 contribute to blood pressure regulation and/or renal damage and (2) the causative gene(s) and pathway(s) can be identified through positional cloning approaches and sequence/expression analysis.;As there were 133 genes and 12,673 single nucleotide variants between SS and BN within the 6.1 Mb candidate region for hypertension and renal disease on rat chromosome 12, smaller sub-congenic strains were developed and characterized in order to physically narrow the list of potential candidate genes and variants. By generating three overlapping sub-congenic strains and excluding regions that did not appear to elevate blood pressure and renal disease, we reduced the candidate region for hypertension and renal disease by 86% to an 830 kb region with 14 genes. Furthermore, we observed indicators of renal damage before the development of hypertension in our rat models.;Whole genome sequencing, whole transcriptome analyses, and qRT-PCR were used to further prioritize candidate genes. Analysis of whole genome sequencing data from several different rat strains showed a 100 kb region with 96 single nucleotide positions where SS had a different allele at every position compared to the normotensive BN, SR (Dahl salt-resistant), and WKY (Wistar Kyoto) rat strains (which all shared the same allele at all 96 positions). Only two genes, Grifin and Chst12, are present within the 100 kb region. Moreover, whole transcriptome and qRT-PCR analyses nominated Grifin and Chst12 as novel candidate genes for hypertension and/or renal disease: Grifin was found to be significantly up-regulated in mesenteric vessels between our smallest congenic and the control SSBN12 strain while Chst12 was significantly down-regulated in congenic mesenteric vessels, renal cortex, and renal medulla compared to the control SSBN12 strain. In addition, sequence, structural, and evolutionary analysis of the Grifin gene showed that the current annotation of the human GRIFIN gene as a pseudogene is incorrect.;Finally, we examined the resistance vasculature of our congenic and consomic control strains prior to the development of hypertension to determine whether there were any functional differences between mesenteric arteries from these strains since both Grifin and Chst12 were found to be differentially expressed in mesenteric vessels. Third order mesenteric arteries from the 6.1 Mb congenic and a smaller congenic strain were significantly more reactive to the vasoconstrictors, phenylephrine and serotonin, compared to the SSBN12 control. No differences in response to the endotheliumdependent (acetylcholine) or endothelium-independent (sodium nitroprusside) vasodilators were observed between congenic and consomic mesenteric arteries. In addition, congenic mesenteric arteries were stiffer and had significantly higher collagen to elastin ratios compared to consomics. In summary, these results showed that congenic mesenteric arteries had enhanced sensitivity to vasoconstrictors and structural differences prior to the development of hypertension.;Collectively, the studies in this dissertation nominated two novel genes, Grifin and Chst12, for hypertension and renal disease, in addition to implicating the resistance vasculature and the renal system as contributors to elevations in blood pressure in our congenic strains in response to high salt diets. Future studies need to validate the role of Grifin and/or Chst12 in hypertension and kidney disease.
机译：高血压是一种疾病，困扰20岁以上的美国成年人，三分之一的成年人高血压病例的特征是原发性或原发性高血压，这意味着血压升高的根本原因尚不清楚。此外，高血压是导致慢性肾脏疾病的主要危险因素之一，在美国影响到16.8％的20岁以上成年人。不幸的是，在高血压和慢性肾脏疾病的治疗和预防方面尚未取得实质性进展，部分是由于它们的遗传复杂性。对近交大鼠模型的研究，例如SS（达尔盐敏感性）高血压和BN（挪威棕色）血压正常大鼠品系，可以帮助剖析高血压和肾脏疾病的基因复杂性。 SS菌株在高盐饮食下会发展为高血压和肾脏损害。先前的研究表明，与SSBN12对照大鼠品系相比，大鼠12号染色体上的6.1 Mb SS区域显着增加了血压和肾脏损害，这是通过将BN大鼠12号染色体转移到SS背景上而得出的。 ：（1）位于大鼠12号染色体上13.41-19.55 Mb之间的一个基因有助于血压调节和/或肾脏损害，并且（2）可以通过位置克隆来鉴定其致病基因和途径由于在大鼠12号染色体上的6.1 Mb高血压和肾脏疾病候选区域中，SS和BN之间存在133个基因和12,673个单核苷酸变异，因此开发了较小的亚同系菌株并进行了表征从物理上缩小潜在候选基因和变体的列表。通过产生三个重叠的亚同系菌株，并排除似乎没有升高血压和肾脏疾病的区域，我们将高血压和肾脏疾病的候选区域减少了86％，减少到具有14个基因的830 kb区域。此外，我们在大鼠模型中观察到了高血压发展之前的肾脏损害指标。;全基因组测序，整个转录组分析和qRT-PCR被用来进一步确定候选基因的优先级。对来自几种不同大鼠品系的全基因组测序数据的分析显示，与正常血压的BN，SR（耐达尔盐）和WKY（Wistar京都）相比，SS在每个位置上具有96个单核苷酸位置的等位基因具有不同的等位基因大鼠品系（在所有96个位置均共享相同的等位基因）。 100 kb区域内仅存在两个基因Grifin和Chst12。此外，全转录组和qRT-PCR分析将Grifin和Chst12提名为高血压和/或肾脏疾病的新候选基因：发现在我们最小的同基因和对照SSBN12菌株之间的肠系膜血管中，Grifin明显上调，而Chst12显着与对照SSBN12菌株相比，在同系肠系膜血管，肾皮质和肾髓质中表达下调。此外，对Grifin基因的序列，结构和进化分析表明，目前人类GRIFIN基因作为假基因的注释是不正确的。最后，我们在开发了Grifin基因之前，检查了我们的同基因和纯体控制菌株的抗脉管系统高血压以确定这些菌株的肠系膜动脉之间是否存在功能差异，因为发现格里芬和Chst12在肠系膜血管中均差异表达。与SSBN12对照相比，来自6.1 Mb同系和较小同系菌株的三阶肠系膜动脉对血管收缩剂，去氧肾上腺素和血清素的反应性明显更高。在同基因和清肠系膜动脉之间，未观察到对内皮依赖性（乙酰胆碱）或内皮依赖性（硝普钠）血管舒张剂的反应差异。此外，与清扫肠系膜相比，同系肠系膜动脉僵硬，胶原蛋白与弹性蛋白的比例明显更高。总之，这些结果表明，在高血压发生之前，同基因肠系膜动脉对血管收缩剂的敏感性和结构差异有所增强。总体而言，本论文的研究提名了两个新的基因Grifin和Chst12用于高血压和肾脏疾病暗示抵抗性脉管系统和肾脏系统是高盐饮食对我们同基因菌株血压升高的贡献。未来的研究需要验证Grifin和/或Chst12在高血压和肾脏疾病中的作用。

著录项

  • 作者

    Prisco, Sasha Zheng.;

  • 作者单位

    The Medical College of Wisconsin.;

  • 授予单位 The Medical College of Wisconsin.;
  • 学科 Biology Physiology.;Biology Genetics.;Biology General.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 324 p.
  • 总页数 324
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 高分子化学（高聚物）;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号