Regulation of Angiogenesis and Renin Expression in Rats

大鼠血管生成和肾素表达的调节

基本信息

  • 批准号:
    7217710
  • 负责人:
  • 金额:
    $ 43.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

A myriad of physiological data confirms that renin is a critical component of the normal angiogenesis response seen in skeletal muscle with electrical stimulation. Using SS-13BN/Mcwi (SS-13BN) consomic rats and a series of congenic rats, we have demonstrated that restoration of a small region surrounding the renin gene confers normal renin levels and restores the normal angiogenic phenotype in the Dahl S (SS) rat. Despite this data, no difference has been observed in the coding region or the classically defined promoter region of the renin gene that would explain the differences in expression. Therefore it is the goal of this application to determine the sequence variants in the region, demonstrate which of these variants impact renin gene regulation in vitro, and using a transgenic approach, demonstrate that this candidate sequence variant eliminates normal renin regulation and the angiogenic phenotype in a subcongenic rat. This will be accomplished through a series of experiments comprising three specific aims. In specific Aim 1, we will begin with a congenic rat line SS.BN- (D13rat123-D13rat101)/Mcwi (referred to as line 9) in which a region of less than 4.5 Mbp surrounding the renin gene region has been introgressed from the BN (Brown Norway) genome onto the SS/JrHsdMcwi (SS) background. Using well-established techniques of marker-assisted selection to identify recombinants, we will reduce this candidate region to 1-2 Mbp. In specific Aim 2, we will identify candidate sequence variants within this reduced region by sequencing the SS and other closely related strains that do not share the antiangiogenic phenotype, including the Dahl salt resistant (SR), the Lyon Normotensive (LN), the Fawn Hooded Hypertensive (FHH) and the BN rats. Using the five strains, we have shown that we can reduce the number of potential causative strain-specific sequence variants within the candidate region to a manageable number, theoretically as low as 10, with a probability of having a false positive candidate mutation remaining below 1%. The candidate variants identified by sequencing and validated by a bioinformatics approach will be tested in vitro. This will be achieved by the use of a cell based system in which endothelial cells derived from the subcongenic line carrying the reduced region (Aim 1) will be transfected with SS Bacterial Artificial Chromosomes (BACs) and renin regulation will be assessed. We will use the surrogate phenotype of serum starvation-induced renin expression to assess the efficacy of the targeted mutation in modulating the renin phenotype. Specific Aim 3 will focus on the final identification and validation of the causative strain-specific sequence variant in this region. Our final experiment will be to use a transgenic rescue approach with a bacterial artificial chromosome transgene harboring the SS allele. Substitution of the allele identified in previous experiments will be performed on the background of the reduced subcongenic to test for confirmation of the loss of the angiogenic phenotype in vivo.
无数的生理数据证实肾素是正常血管生成反应的关键组成部分 在具有电刺激的骨骼肌中可见。使用SS-130亿/MCWI(SS-130亿)综合大鼠和一系列 在同类大鼠中,我们证明了肾素基因周围的小区域的恢复 正常肾素水平并恢复DAHL S(SS)大鼠的正常血管生成表型。尽管有这些数据,否 在编码区域或肾素基因的经典启动子区域中观察到差异 这将解释表达的差异。因此,确定该应用程序的目的是 该区域的序列变体证明了这些变体在体外影响肾素基因调节,并且 使用转基因方法,证明该候选序列变体消除了正常的肾素 亚综合大鼠的调节和血管生成表型。这将通过一系列 实验包括三个特定目标。在特定的目标1中,我们将从先天大鼠线开始。 (D13RAT123-D13RAT101)/MCWI(称为第9行),其中一个小于4.5 MBP周围的区域 肾素基因区域已从BN(Brown Norway)基因组渗入SS/JRHSDMCWI(SS) 背景。使用公认的标记辅助选择技术来识别重组,我们将 将该候选区域减少到1-2 MBP。在特定目标2中,我们将确定候选序列变体 通过对不具有抗血管生成的SS和其他密切相关的菌株进行测序来减少区域 表型,包括耐达尔盐(SR),里昂正常性(LN),小鹿戴 高血压(FHH)和BN大鼠。使用五个菌株,我们表明我们可以减少 候选区域内潜在的因果应变特异性序列变体可管理数字, 从理论上讲,低至10,其假阳性候选突变的可能性保持在1%以下。 通过测序确定并通过生物信息学方法验证的候选变体将在体外测试。 这将通过使用基于细胞的系统来实现,在该系统中,内皮细胞从 携带还原区域(AIM 1)的亚替香料线将用SS细菌人工转染 将评估染色体(BAC)和肾素调节。我们将使用血清的替代表型 饥饿诱导的肾素表达,以评估靶突变调节肾素的功效 表型。具体目标3将重点介绍最终识别和验证因果菌株特异性的 该区域中的序列变体。我们的最后实验是使用转基因救援方法 带有SS等位基因的细菌人造染色体转基因。在 先前的实验将在降低的亚修月的背景下进行,以测试确认 体内血管生成表型的丧失。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ANDREW S. GREENE其他文献

ANDREW S. GREENE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ANDREW S. GREENE', 18)}}的其他基金

Epigenomes and Epigenetic Mechanisms in BP-relevant Tissues
BP相关组织的表观基因组和表观遗传机制
  • 批准号:
    10460346
  • 财政年份:
    2020
  • 资助金额:
    $ 43.81万
  • 项目类别:
Epigenomes and Epigenetic Mechanisms in BP-relevant Tissues
BP相关组织的表观基因组和表观遗传机制
  • 批准号:
    10023346
  • 财政年份:
    2020
  • 资助金额:
    $ 43.81万
  • 项目类别:
Epigenomes and Epigenetic Mechanisms in BP-relevant Tissues
BP相关组织的表观基因组和表观遗传机制
  • 批准号:
    10667384
  • 财政年份:
    2020
  • 资助金额:
    $ 43.81万
  • 项目类别:
Epigenomes and Epigenetic Mechanisms in BP-relevant Tissues
BP相关组织的表观基因组和表观遗传机制
  • 批准号:
    10238140
  • 财政年份:
    2020
  • 资助金额:
    $ 43.81万
  • 项目类别:
Research Services Core
研究服务核心
  • 批准号:
    8230996
  • 财政年份:
    2011
  • 资助金额:
    $ 43.81万
  • 项目类别:
Inflammation and Infection in Acquired & Congenital Cardiovascular Disease
获得性炎症和感染
  • 批准号:
    8426136
  • 财政年份:
    2009
  • 资助金额:
    $ 43.81万
  • 项目类别:
Inflammation and Infection in Acquired and Congenital Cardiovascular Disease
获得性和先天性心血管疾病的炎症和感染
  • 批准号:
    8055920
  • 财政年份:
    2009
  • 资助金额:
    $ 43.81万
  • 项目类别:
Inflammation and Infection in Acquired and Congenital Cardiovascular Disease
获得性和先天性心血管疾病的炎症和感染
  • 批准号:
    8255619
  • 财政年份:
    2009
  • 资助金额:
    $ 43.81万
  • 项目类别:
Inflammation and Infection in Acquired and Congenital Cardiovascular Disease
获得性和先天性心血管疾病的炎症和感染
  • 批准号:
    7693979
  • 财政年份:
    2009
  • 资助金额:
    $ 43.81万
  • 项目类别:
Inflammation and Infection in Acquired and Congenital Cardiovascular Disease
获得性和先天性心血管疾病的炎症和感染
  • 批准号:
    7817140
  • 财政年份:
    2009
  • 资助金额:
    $ 43.81万
  • 项目类别:

相似国自然基金

细胞免疫与肾脏局部RAAS系统对话在盐敏感者肾脏钠代谢障碍中的作用机制研究
  • 批准号:
    81370357
  • 批准年份:
    2013
  • 资助金额:
    70.0 万元
  • 项目类别:
    面上项目
肾素-血管紧张素-醛固酮系统对高血压并发糖尿病的作用分析
  • 批准号:
    81000110
  • 批准年份:
    2010
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目
肾素-血管紧张素-醛固酮系统在围产期体钠失衡程控子代咸味觉感受功能及高血压发病中的作用
  • 批准号:
    31000518
  • 批准年份:
    2010
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    7766231
  • 财政年份:
    2010
  • 资助金额:
    $ 43.81万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8213466
  • 财政年份:
    2010
  • 资助金额:
    $ 43.81万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8435332
  • 财政年份:
    2010
  • 资助金额:
    $ 43.81万
  • 项目类别:
Physiologic effects of natriuretic peptide genetic variation
利尿钠肽遗传变异的生理效应
  • 批准号:
    8011974
  • 财政年份:
    2010
  • 资助金额:
    $ 43.81万
  • 项目类别:
Transcriptional regulation of human angiotensin receptor
人血管紧张素受体的转录调控
  • 批准号:
    7658752
  • 财政年份:
    2006
  • 资助金额:
    $ 43.81万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了