Oxidative Stress, Hypertension and an FGF-binding Protein

氧化应激、高血压和 FGF 结合蛋白

基本信息

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
项目类别：
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

项目摘要

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（FGF-1 或 -2）在大多数正常组织中以显着浓度存在成人。然而，这些 FGF 以非活性状态固定在细胞外基质上，仅人们对它们如何溶解和激活以到达细胞外受体知之甚少。一 FGF 动员的机制是通过与分泌性结合蛋白 (BP) 结合，我们研究表明 BP1 可以增强本地储存的固定化 FGF 的活性。 BP1表达受到控制通过培养细胞中的应激途径，发现在受伤、中毒或感染性损伤后表达上调皮肤或肾脏。携带诱导型 BP1 转基因的小鼠中 BP1 表达导致转基因诱导和分析后两天内平均动脉血压 (MAP) 增加 +30 mm Hg 血管收缩性显示出对血管紧张素II的敏感性。 BP1转基因后MAP的升高全身施用超氧化物歧化酶模拟物 Tempol 可抑制表达表明氧化应激的重要作用。我们假设 BP1/FGF 信号调节血管对收缩信号的敏感性，并建议根据以下目标进行研究：目的 1. 评估 FGF-2 或其他 FGF 对 BP1 诱导的高血压作用的贡献。我们将研究与 FGF-2(-/-) 杂交的小鼠的血压、血管收缩力和肾小管功能携带诱导型 BP1 转基因的小鼠。 BP1 和 FGF-2 的全身给药将对此进行补充。目的 2. 研究肾脏表达 BP1 对血压调节、血管收缩性和肾小管功能，我们将使用携带 HoxB7 控制的四环素诱导型小鼠 BP1转基因。为了评估内源性 BP1 对氧化应激调节血压的作用，我们将生成 BP1 表达无效的小鼠。目标 3. 研究 BP1/FGF 信号传导与 G 蛋白偶联受体之间的细胞内串扰我们将监测肾小球前平滑肌细胞的信号转导和表型效应来自实验动物。通过已知的通路整合器（即 MAPK）进行生化信号传导和增殖/细胞存活和超氧化物生成将用作读数。质谱鉴定串扰中的新信号蛋白将对此进行补充。