Guanylyl cyclase receptors: Targets for medical intervention

鸟苷酸环化酶受体：医疗干预的目标

基本信息

批准号：
7333226
负责人：
JOSEPH P ALBANESI
金额：
$ 34.54万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2006-02-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7333226
关键词：
Acute Adipocytes Adipose tissue Americas Angioplasty Animals Arteries Atherosclerosis Body Weight Breeding C-Type Natriuretic Peptide Cell Line Cells Chondrocytes Clinic Complement Condition Diet Disease Disruption Dwarfism Eating Embryo Fatty acid glycerol esters Fibroblasts Figs - dietary GTP-Binding Proteins Genes Genetic Genetic Models Genome Genomics Guanylate Cyclase Health Hippocampus (Brain)Hypertension Hypertrophy Immunoprecipitation In Vitro Inhibition of Cell Proliferation Intervention Knock-out Knockout Mice Lesion Life Ligands Lipolysis Liver Liver diseases Mediating Medical Membrane Molecular Molecular Target Mus Natriuretic Peptides Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Obesity Pathway interactions Phenotype Phosphorylation Phosphorylation Site Physiological Principal Investigator Procedures Protein Dephosphorylation Protein Kinase Protein phosphatase Proteins Protocols documentation Receptor Activation Receptor Gene Receptor Signaling Regulation Research Research Personnel Risk Factors Role Scheme Serum Severities Signal Pathway Signal Transduction Small Interfering RNA Sphingosine-1-Phosphate Receptor Standards of Weights and Measures Therapeutic Tissues Transgenes Transgenic Organisms Translations Work Wound Healing Yeasts adipocyte differentiation analog atrial natriuretic factor receptor B autocrine base bone dentate gyrus desensitization established cell line human disease in vivo knock-down mouse model paracrine peptide A programs promoter receptor receptor expression research study response restenosis sphingosine 1-phosphate subcutaneous yeast two hybrid system

项目摘要

We will define the functions of GCB (NPR-B), a membrane guanylyl cyclase receptor activated by the local paracrine/autocrine ligand, C-type natriuretic peptide (CNP). GCB is highly expressed in chondrocytes, adipocytes and fibroblasts; GCB activation usually leads to an inhibition of cell proliferation and hypertrophy. We recently identified sphingosine-1 -phosphate (S1P) as a potent, effective and highly specific GCB desensitization factor. The first specific aim concentrates on the molecular pathway by which S1P specifically induces GCB desensitization. These studies are important in that CNP, which acts as an antagonist to S1P, is strongly implicated as having an important role in tissue remodeling, including atherosclerosis, restenosis following angioplasty, and even liver disease. Mouse genetic models, siRNA and interaction trap screens (immunoprecipitation, yeast two hybrid, Sos-Ras) will define proteins that mediate the S1P-induced desensitization of GCB. In preliminary research we have already identified various candidate GCB-associated proteins. These proteins will themselves be used in interaction trap screens to define other molecules within the S1P-GCB desensitization pathway. Desensitization of GCB is ultimately regulated by dephosphorylation of the receptor, and therefore the protein kinase/protein phosphatase responsible for GCB regulation will be purified, identified and mechanisms of regulation determined. We also have disrupted the GCB gene, and then corrected a severe dwarfism by expression of GCB specifically in chondrocytes in the null background. These GCB animals contained almost no fat compared to wild-type littermates. Therefore, the second specific aim concentrates on the functional roles of GCB in fibroblasts and adipocytes. We will compare the effects of various treatments (in vitro and in vivo) on fibroblast and adipocyte function, with particular emphasis on the role of GCB in tissue remodeling after wounding and in adipocyte differentiation. The proposed studies will have significant and substantial implications in human disease, since one of the largest health problems in America is obesity, often caused by an over-abundance of fat cells. Obesity is a high risk factor for non insulin-dependent diabetes and hypertension. Thus, the proposed research impacts on some of our most important medical issues, including wound repair, atherosclerosis, restenosis following angioplasty, and a host of diseases associated with obesity.

我们将定义 GCB (NPR-B) 的功能，GCB 是一种由局部细胞激活的膜鸟苷酸环化酶受体。旁分泌/自分泌配体，C 型利钠肽 (CNP)。 GCB 在软骨细胞中高表达，脂肪细胞和成纤维细胞； GCB 激活通常会抑制细胞增殖和肥大。我们最近发现 1-磷酸鞘氨醇 (S1P) 是一种强效、有效且高度特异性的 GCB 脱敏因素。第一个具体目标集中于 S1P 的分子途径特异性诱导 GCB 脱敏。这些研究对于 CNP 很重要，CNP 充当了 S1P 拮抗剂，在组织重塑中具有重要作用，包括动脉粥样硬化、血管成形术后再狭窄，甚至肝脏疾病。小鼠遗传模型、siRNA 和相互作用陷阱筛选（免疫沉淀、酵母二杂交、Sos-Ras）将定义介导的蛋白质 S1P诱导的GCB脱敏。在初步研究中，我们已经确定了各种候选 GCB 相关蛋白。这些蛋白质本身将用于相互作用陷阱屏幕定义 S1P-GCB 脱敏途径中的其他分子。 GCB的脱敏最终是由受体的去磷酸化调节，因此由蛋白激酶/蛋白磷酸酶调节负责 GCB 监管的职责将被纯化、确定并确定监管机制。我们也破坏了 GCB 基因，然后通过在体内特异性表达 GCB 来纠正严重的侏儒症空背景中的软骨细胞。与野生型相比，这些 GCB 动物几乎不含脂肪同窝的。因此，第二个具体目标集中在 GCB 在成纤维细胞和脂肪细胞。我们将比较各种治疗（体外和体内）对成纤维细胞和脂肪细胞功能，特别强调 GCB 在受伤后组织重塑中的作用以及脂肪细胞分化。拟议的研究将对人类产生重大和实质性的影响疾病，因为美国最大的健康问题之一是肥胖，通常是由过度摄入引起的脂肪细胞。肥胖是非胰岛素依赖型糖尿病和高血压的高危因素。因此，拟议的研究对我们一些最重要的医学问题的影响，包括伤口修复，动脉粥样硬化、血管成形术后再狭窄以及许多与肥胖相关的疾病。