Analysis of ACE Knockout Mice

ACE 基因敲除小鼠的分析

• 批准号: 7619701
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 7.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619701
• 关键词: Abnormal Macrophage; Amino Acids; Anemia; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animal Model; Animals; Binding; Biochemistry; Blood Pressure; Blood Vessels; Bradykinin; Brain region; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cells; Cleaved cell; Clinical Research; Complex; Data; Development; Diabetic Nephropathy; Dipeptides; Electrolytes; Endothelium; Engineering; Enzymes; Epithelium; Figs - dietary; Fluid Balance; Functional disorder; Genetic Techniques; Grant; Heart failure; Histocompatibility Testing; Human; Hypertension; Hypotension; Immune response; Injury; Kidney; Kidney Diseases; Knockout Mice; Literature; Liver; Lung; Measures; Modeling; Mus; Organ; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Pharmacologic Substance; Phenotype; Physiological; Physiology; Plasma; Play; Production; Proteins; Proximal Kidney Tubules; Renal function; Renin; Renin-Angiotensin System; Research; Research Personnel; Role; Seminal; Series; Serum; Substrate Specificity; Tail; Testis; Tissues; Vascular Endothelium; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilator Agents; Work; Zinc; blood pressure regulation; enzyme activity; enzyme structure; expectation; hemodynamics; hypertension treatment; kidney vascular structure; macrophage; male; mouse model; peptidyl-dipeptidase Dcp; reproductive; success

DESCRIPTION (provided by applicant): Angiotensin converting enzyme (ACE) is a peptidase that converts the inactive precursor angiotensin I into angiotensin II; it plays a critical role in regulating cardiovascular and renal function. During the last 4 years, we continued to characterize the physiology of ACE knockout mice. Also, we used genetic techniques to create a series of unique mouse models expressing ACE in very selected tissue-types. In the first portion of the grant, we discuss our progress in characterizing mice with 1) no ACE expression, and 2) ACE expression restricted to selected tissues, such as the liver. This work showed that, contrary to expectations, endothelial expression of ACE is not necessary for normal blood pressure and renal concentrating ability. In the second portion of the grant, we present preliminary data characterizing a mouse line engineered to express ACE only in macrophages (called ACE 10/10). These animals appear hyper responsive to vascular injury as measured in a model of carotid injury. The first Specific Aim is to continue to characterize the physiology and macrophage function of the ACE 10/10 mice. ACE 10/10 mice over-express ACE in macrophages; ACE 3/3 mice have no macrophage ACE. Using these animal models, we propose to study the specific role of macrophage and endothelial ACE production in two models of vascular injury (Aim 2) and in two models of progressive renal disease (Aim 3). This work reflects the enormous literature suggesting a role of angiotensin II in both human vascular and renal injury. Our hope is to understand the contributions of endothelium vs. macrophage ACE to the pathophysiology of this injury.

描述（申请人提供）：血管紧张素转化酶（ACE）是一种将无活性的前体血管紧张素I转化为血管紧张素II的肽酶；它在调节心血管和肾功能中起着至关重要的作用。在过去 4 年中，我们继续表征 ACE 基因敲除小鼠的生理学特征。此外，我们还利用遗传技术创建了一系列独特的小鼠模型，在精选的组织类型中表达 ACE。在拨款的第一部分，我们讨论了我们在表征小鼠方面取得的进展：1）无 ACE 表达，2）ACE 表达仅限于选定的组织，例如肝脏。这项工作表明，与预期相反，ACE 的内皮表达对于正常血压和肾脏浓缩能力并不是必需的。在资助的第二部分中，我们提供了初步数据，描述了仅在巨噬细胞中表达 ACE 的小鼠品系（称为 ACE 10/10）。根据颈动脉损伤模型的测量，这些动物似乎对血管损伤反应过度。第一个具体目标是继续表征 ACE 10/10 小鼠的生理学和巨噬细胞功能。 ACE 10/10 小鼠巨噬细胞过度表达 ACE； ACE 3/3 小鼠没有巨噬细胞 ACE。使用这些动物模型，我们建议研究巨噬细胞和内皮 ACE 产生在两种血管损伤模型（目标 2）和两种进行性肾病模型（目标 3）中的具体作用。这项工作反映了大量文献表明血管紧张素 II 在人类血管和肾脏损伤中的作用。我们希望了解内皮细胞与巨噬细胞 ACE 对这种损伤的病理生理学的贡献。