Oxidative Stress, Hypertension and an FGF-binding Protein

氧化应激、高血压和 FGF 结合蛋白

• 批准号: 7218285
• 负责人: Anton Wellstein
• 金额: $ 33.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218285
• 关键词: AIDS-Associated Nephropathy; Acute Kidney Failure; Address; Adult; Angiotensin II; Animals; Binding; Binding Proteins; Biochemical; Blood Pressure; Blood Vessels; Cell Survival; Cells; Chemical Injury; Circadian Rhythms; Complement; Cultured Cells; Development; Endothelium; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; Fibroblast Growth Factor; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Figs - dietary; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Expression; Generations; Human; Hypertension; Immunoprecipitation; In Vitro; Injury; Kidney; Knockout Mice; MAPK14 gene; MAPK8 gene; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mesenchymal; Mitogen-Activated Protein Kinases; Modeling; Monitor; Mus; Normal tissue morphology; Organ; Oxidative Stress; Pathway interactions; Patients; Proteins; Reactive Oxygen Species; Reading; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research Design; Research Personnel; Role; Sampling; Series; Signal Transduction; Signal Transduction Alteration; Signaling Protein; Skin; Smooth Muscle Myocytes; Stress; Superoxide Dismutase; Superoxides; Tetracycline; Tetracycline Control; Tetracyclines; Tissues; Transgenes; Transgenic Mice; Tubular formation; Two-Dimensional Gel Electrophoresis; Up-Regulation; Work; Wound Healing; blood pressure regulation; cell type; day; experimental analysis; extracellular; in vivo; mimetics; permanent cell line; programs; receptor; repaired; research study; response; role model; selective expression; tempol; transgene expression

Fibroblast growth factors (FGF-1 or -2) are present at significant concentrations in most normal tissues in the adult. However, these FGFs are immobilized in an inactive state on the extracellular matrix and it is only poorly understood how they are solubilized and activated to reach their extracellular receptors. One mechanism through which FGFs can be mobilized is by binding to secreted binding proteins (BPs) and we showed that BP1 can enhance the activity of locally stored, immobilized FGFs. BP1 expression is controlled by stress pathways in cultured cells and found upregulated after wounding, toxic or infectious injury of the skin or kidneys. BP1 expression in mice carrying an inducible BP1 transgene caused a significant rise in mean arterial blood pressure (MAP) by +30 mm Hg within two days of transgene induction and analysis of vascular contractility showed a sensitization to angiotensin II. The rise of MAP after BP1 transgene expression was inhibited by systemic administration of the superoxide dismutase mimetic Tempol suggesting an essential role of oxidative stress. We hypothesize that BP1/FGF signaling modulates the sensitivity of blood vessels towards contractile signaling and propose to study this under the following aims: Aim 1. To evaluate the contribution of FGF-2 or other FGFs to the BP1-induced hypertensive effect. We will study blood pressure, vessel contractility and renal tubular function in FGF-2(-/-) mice that are crossed with mice carrying an inducible BP1 transgene. Systemic administration of BP1 and FGF-2 will complement this. Aim 2. To study the contribution of kidney expression of BP1 to blood pressure regulation, vessel contractility and renal tubular function we will use mice harboring a HoxB7-controlled, tetracycline inducible BP1 transgene. To evaluate the role of endogenous BP1 to oxidative stress-regulated blood pressure, we will generate mice that are null for BP1 expression. Aim 3. To study the intracellular cross-talk between BP1 / FGF signaling and G-protein coupled receptor pathways we will monitor signal transduction and phenotypic effects in preglomular smooth muscle cells from experimental animals. Biochemical signaling via known integrators of the pathways (i.e. MAPKs) and proliferation/cell survival and superoxide generation will be used as read-outs. Mass spectrometry to identify new signaling proteins in the cross-talk will complement this.

成纤维细胞生长因子(成纤维细胞生长因子-1或成纤维细胞生长因子-2)在大多数正常组织中有显著浓度。 成年人。然而，这些FGFs是以非活性状态固定在细胞外基质上的，它只是 对它们如何被溶解和激活以到达它们的细胞外受体知之甚少。一 FGFs的动员机制是通过与分泌结合蛋白(BPS)和WE结合 结果表明，BP1可以增强本地储存的固定化FGFs的活性。BP1的表达受到控制 通过培养细胞中的应激途径，并在创伤、毒性或感染性损伤后发现上调 皮肤或肾脏。携带可诱导BP1转基因小鼠的BP1表达显著增加 转基因诱导后两天内平均动脉压(MAP)的变化及分析 血管收缩功能对血管紧张素II敏感。BP1转基因后MAP的升高 全身性给药抑制超氧化物歧化酶模拟物Tempol1的表达 暗示了氧化应激的重要作用。我们假设BP1/成纤维细胞生长因子信号调节 血管对收缩信号的敏感性，并建议在以下目标下进行研究： 目的1.探讨成纤维细胞生长因子-2或其他成纤维细胞生长因子在BP1诱导的高血压效应中的作用。我们会 与成纤维细胞生长因子-2(-/-)杂交的小鼠血压、血管收缩功能和肾小管功能的研究 携带可诱导BP1转基因的小鼠。全身应用BP1和成纤维细胞生长因子-2将补充这一点。 目的：研究BP1在肾脏中的表达在血压调节、血管生成中的作用。 收缩能力和肾小管功能我们将使用携带HoxB7控制的四环素诱导物的小鼠 BP1转基因。为了评估内源性BP1在氧化应激调节血压中的作用，我们 将产生BP1表达为空的小鼠。 目的3.研究BP1/成纤维细胞生长因子信号通路与G蛋白偶联受体之间的细胞内相互作用 我们将监测肾小球前平滑肌细胞的信号转导和表型效应的途径 从实验动物身上。通过已知的通路整合子(即MAPK)和 增殖/细胞存活和超氧化物生成将被用作读出。质谱学用于鉴定 串扰中的新信号蛋白将补充这一点。