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中文摘要
翻译
在美国,肾血管性高血压是发病率和死亡率的主要原因。最优 肾动脉狭窄(RAS)患者的治疗在很大程度上是一个有争议的话题。 部分原因是心血管和肾脏疾病发生的基本信号机制 RAS的设置还没有被很好地理解。单侧RAS已被用作人类的模型 肾血管性高血压。这种病变会导致血管肥大和硬化,间质纤维化, 肾小管萎缩、肾小管间质炎症和代偿性肥大 对侧肾。这项计划项目申请的中心假设是,形态 单侧RAS后狭窄和对侧肾脏的改变由血流动力学触发 病变,狭窄肾脏的组织缺氧,氧化。应激与肾素-血管紧张素的激活 系统。这些“启动因素”是项目1、2和4的主要关注点。 在项目3中测试的是,这些“启动因子”负责诱导转化生长因子-β,即细胞周期 抑制物p21和p27,以及MAPK通路,它们在狭窄和狭窄中受到差异调节。 对侧肾。在特定的目标1中,我们将检验转化生长因子-β、p21/p27和p-ERK是 在狭窄的肾脏持续升高,导致间质纤维化和肾小管萎缩,并 对侧肾脏一过性升高,导致代偿性肥大/增生。具体而言 目的通过使用转化生长因子-β1中和抗体和小鼠阻断转化生长因子-β1信号转导。 携带Smads基因的纯合缺失,Smads基因是转化生长因子-β1信号转导的必要中间产物,以测试 假设转化生长因子-β在狭窄肾和肾萎缩的发生发展中起中心作用 对侧肾脏代偿性肥大/增生。在具体目标3中,我们将采用p21和 P27基因敲除小鼠,以测试p21和/或p27缺失将限制间质范围的假设 在狭窄的肾脏中的纤维化,并将促进肥大而不是肥大的反应 对侧肾。最后,我们将测试抑制ERK或其他MAPK通路将 限制狭窄肾间质纤维化的发展和代偿性肥大和/或 对侧肾脏的增生。拟议的研究将定义信令的关键要素 由RAS触发的通路,可能为干预提供机制基础 阻止肾血管性高血压患者发生不可逆性肾损伤。
英文摘要
Renovascular hypertension is a major cause of morbidity and mortality in the United States. Optimal management of patients with renal artery stenosis (RAS) is a subject of considerable controversy, in large part because basic signaling mechanisms underlying the development of cardiovascular and renal disease in the setting of RAS are not well understood. Unilateral RAS has been employed as a model of human renovascular hypertension. This lesion induces vascular hypertrophy and sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation in the stenotic kidney and compensatory hypertrophy in the contralateral kidney. The central hypothesis of this Program Project application is that the morphologic alterations in the stenotic and contralateral kidneys following unilateral RAS are triggered by hemodynamic alterations, tissue hypoxia in the stenotic kidney, oxidative. stress, and activation of the renin-angiotensin system. These "initiating factors" are the primary focus of Projects 1, 2, and 4. The overall hypothesis to be tested in Project 3 is that these "initiating factors" are responsible for induction of TGF-p, the cell cycle inhibitors p21 and p27, and the MAPK pathways, which are differentially regulated in the stenotic and contralateral kidney. In Specific Aim 1, we will test the hypothesis that TGF-p, p21/p27, and p-ERK are persistently elevated in the stenotic kidney, leading to interstitial fibrosis and tubular atrophy, and are transiently elevated in the contralateral kidney, leading to compensatory hypertrophy/hyperplasia. In Specific Aim 2, TGF-pl signaling will be interrupted through the use of TGF-p1 neutralizing antibodies and mice bearing homozygous deletion of the SmadS gene, an essential intermediate in TGF-pl signaling, to test the hypothesis that TGF-p plays a central role in the development of renal atrophy in the stenotic kidney and compensatory hypertrophy/hyperplasia in the contralateral kidney. In Specific Aim 3, we will employ p21 and p27 knockout mice to test the hypothesis that deletion of p21 and/or p27 will limit the extent of interstitial fibrosis in the stenotic kidney and will promote a hyperplastic rather than hypertrophic response in the contralateral kidney. Finally, we will test the hypothesis that inhibition of ERK or other MAPK pathways will limit the development of interstitial fibrosis in the stenotic kidney and compensatory hypertrophy and/or hyperplasia in the contralateral kidney. The proposed studies will define critical elements of signaling pathways triggered by RAS and may provide the mechanistic basis for interventions directed towards arresting the development of irreversible renal injury in patients with renovascular hypertension.
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Role of CC chemokine signaling in hyperglycemic renal artery stenosis
  • 批准号:
    9012745
  • 项目类别:
  • 资助金额:
    $48.06万
  • 财政年份:
    2013
  • 负责人:
    JOSEPH PETER GRANDE
  • 依托单位:
Role of CC chemokine signaling in hyperglycemic renal artery stenosis
  • 批准号:
    8502985
  • 项目类别:
  • 资助金额:
    $45.74万
  • 财政年份:
    2013
  • 负责人:
    JOSEPH PETER GRANDE
  • 依托单位:
Role of CC chemokine signaling in hyperglycemic renal artery stenosis
  • 批准号:
    9215631
  • 项目类别:
  • 资助金额:
    $47.39万
  • 财政年份:
    2013
  • 负责人:
    JOSEPH PETER GRANDE
  • 依托单位:
Role of CC chemokine signaling in hyperglycemic renal artery stenosis
  • 批准号:
    8634016
  • 项目类别:
  • 资助金额:
    $48.72万
  • 财政年份:
    2013
  • 负责人:
    JOSEPH PETER GRANDE
  • 依托单位:
海外基金