GENETIC VARIANTS IN RENIN ANGIOTENSIN SYSTEM IN PEDIATRIC RENAL DISEASE

小儿肾病中肾素血管紧张素系统的基因变异

• 批准号: 6301133
• 负责人: VALENTINA KON
• 金额: $ 15.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301133
• 关键词: cell line; clinical research; enzyme activity; gene expression; genetic mapping; genetic polymorphism; genetic regulatory element; genetically modified animals; genotype; glomerulonephritis; human subject; laboratory mouse; nephrotic syndrome; peptidyl dipeptidase A; phenotype; plasminogen activator inhibitors; renin angiotensin system; site directed mutagenesis; tissue inhibitor of metalloproteinases; urinary tract disorder

Renin angiotensin system (RAS) is well established as having a crucial role in cardiovascular and renal diseases. Most persuasive are the accumulating data in animal models as well as in clinical trials affirming the renoprotective effects of antagonizing angiotensin II (Ang II) generation or actions. Interestingly, RAS activity can be modulated by genetic variations of RAS components. In particular, an insertion/deletion polymorphism (I/D) in the human angiotensin I converting enzyme (ACE) gene affects the level of circulating ACE; moreover, homozygous deletion (DD) predicts several cardiovascular disease and progressive deterioration in some glomerular disease, including IgA and diabetic nephropathies. Our projects will test the hypothesis that genetic variations in RAS, particularly the ACE I/D variant, predicts progressive renal damage in a non-glomerular injury, namely congenital uropathies, where RAS has a crucial role. This entity is an important cause of renal damage in children. We further plan to define pathways by which the genetic variant influences downstream events pivotal in progressive renal damage. In view of the apparant heterogeneity in the impact of ACe I/D on ACE activity among organs, we hypothesize that there is a tighter association between ACE polymorphism and renal (vs systemic) ACE activity. Moreover, the purpose that ACE I/D drives other Ang-mediated factors important in tissue damage such as proteinases, e.g., plasminogen activator inhibitor (PAI) and tissue inhibitor of metalloproteinase (TIMP), The hypothesis that local renal ACE (and downstream modulators PAI/TIMP) is pivotal in the renal response to injury will be directly studies in a genetically engineered mouse characterized by regional difference in levels of ACE activity. Finally, mutagenesis studies in human cell lines will define the functional consequence of a putative regulatory element in the ACE I/D locus.

肾素血管紧张素系统（RAS）已被确定为具有 在心血管和肾脏疾病中的关键作用。 最有说服力的 动物模型和临床中的数据是否累积 验证拮抗作用的重新保护作用的试验 血管紧张素II（ANG II）产生或作用。 有趣的是，拉斯 活性可以通过RAS成分的遗传变异来调节。 特别是，插入/缺失多态性（I/D） 人血管紧张素I转化酶（ACE）基因会影响 循环王牌的水平；此外，纯合缺失（DD） 预测几种心血管疾病和进行性降解 在某些肾小球疾病中，包括IgA和糖尿病 肾病。 我们的项目将检验遗传的假设 RAS的变化，特别是ACE I/D变体，预测 非斜体损伤中的进行性肾脏损害，即 先天性泌尿病，RAS具有至关重要的作用。 这个实体是 儿童肾脏损害的重要原因。 我们进一步计划 定义遗传变异影响下游的途径 渐进性肾脏损害的事件关键。 鉴于 ACE I/D对ACE活动的影响的明显异质性 在器官中，我们假设有一个更紧密的关联 在ACE多态性和肾脏（VS系统性）ACE活性之间。 而且，ACE I/D驱动其他Ang介导的目的 在组织损伤（例如蛋白酶，例如）中重要的因素 纤溶酶原激活物抑制剂（PAI）和组织抑制剂 金属蛋白酶（TIMP），局部肾脏ACE的假设 （和下游调制器PAI/TIMP）在肾脏中是关键的 对损伤的反应将直接在遗传上进行研究 工程鼠标的特征是区域差异 ACE活动。 最后，人类细胞系中的诱变研究将 定义推定调节元件的功能结果 在ACE I/D基因座。