Role of FKBP12/12.6 in Endothelial Function

FKBP12/12.6 在内皮功能中的作用

基本信息

批准号：
7320563
负责人：
BRETT M MITCHELL
金额：
$ 26.83万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7320563
关键词：
2-aminoethoxydiphenyl borate Acute Adverse effects Affect Agonist Binding Biological Assay Blood Pressure Blood Vessels Calcineurin Calcium Cardiac Cardiovascular Diseases Cardiovascular system Caveolae Cell membrane Characteristics Coupling Data Dilator Dose Elevation Endothelial Cells Endothelium Enzymes Excision Exhibits FK506 FKBP1B gene Fluorescence Functional disorder Future Genetic Goals Graft Rejection High Blood Pressure Homeostasis Hypertension ITPR1 gene Immune system Immunoblotting Immunosuppressive Agents In Vitro Incidence Knockout Mice Laboratories Link Location Measurement Measures Mediating Modeling Molecular Mus Muscle Fibers Mutant Strains Mice Mutation Nitric Oxide Nitric Oxide Synthase Organ Organ Transplantation Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Production Protein Kinase C Proteins Relative (related person)Research Research Personnel Role Ryanodine Ryanodine Receptor Calcium Release Channel Signal Transduction Signal Transduction Pathway Sirolimus Site Source Tacrolimus Binding Protein 1A Tacrolimus Binding Proteins Tail Techniques Telemetry Testing Therapeutic Transplant Recipients Transplantation Work blood pressure regulation extracellular human FRAP1 protein human NOS3 protein in vivo programs release of sequestered calcium ion into cytoplasm

项目摘要

DESCRIPTION (provided by applicant): Immunosuppressive drugs reduce the incidence of organ rejection following transplantation, however these drugs can cause endothelial dysfunction and hypertension. Our long-term goal is to elucidate the mechanisms by which the immunosuppressive drugs rapamycin and FK506 decrease nitric oxide (NO) and increase blood pressure so that future drugs can be developed that do not promote hypertension and cardiovascular disease. We hypothesize that these effects arise from removal of FKBP12/12.6 from intracellular calcium release channels resulting in increased basal endothelial cell calcium levels and phosphorylation of endothelial NO synthase (eNOS). To test this hypothesis we will: 1) Determine the effects of FKBP12/12.6 depletion on intracellular calcium homeostasis, 2) Determine the role of cPKC in eNOS phosphorylation, NO production, and blood pressure elevation following alterations of FKBP12/12.6, and 3) Assess the role of FKBP12/12.6 in endothelial function and blood pressure regulation. We will use a combination of pharmacologic and/or genetic perturbations of FKBP12/12.6 and measure the effects on blood pressure, endothelium-dependent dilation, NO production, and eNOS and PKC expression and phosphorylation. We will also measure how FKBP12/12.6 depletion in endothelial cells alters intracellular calcium homeostasis including changes in the magnitude, duration, and location of intracellular calcium mobilization. Drugs that suppress the immune system are extremely important following organ transplantation, however these drugs can cause high blood pressure. Our research will use various genetically altered mice and techniques to understand the mechanisms of how this happens in hopes of developing future immunosuppressive drugs that will not have negative cardiovascular side effects.

描述（申请人提供）：免疫抑制药物可降低移植后器官排斥的发生率，但这些药物可导致内皮功能障碍和高血压。我们的长期目标是阐明免疫抑制药物雷帕霉素和 FK506 降低一氧化氮 (NO) 和升高血压的机制，以便未来开发出不会促进高血压和心血管疾病的药物。我们假设这些效应是由于从细胞内钙释放通道中去除 FKBP12/12.6 导致基底内皮细胞钙水平增加和内皮 NO 合酶 (eNOS) 磷酸化所致。为了检验这一假设，我们将：1) 确定 FKBP12/12.6 消耗对细胞内钙稳态的影响，2) 确定 FKBP12/12.6 改变后 cPKC 在 eNOS 磷酸化、NO 产生和血压升高中的作用，以及 3)评估 FKBP12/12.6 在内皮功能和血压调节中的作用。我们将结合使用 FKBP12/12.6 的药理和/或遗传扰动，并测量其对血压、内皮依赖性扩张、NO 产生以及 eNOS 和 PKC 表达和磷酸化的影响。我们还将测量内皮细胞中 FKBP12/12.6 的消耗如何改变细胞内钙稳态，包括细胞内钙动员的幅度、持续时间和位置的变化。抑制免疫系统的药物在器官移植后极其重要，但这些药物可能导致高血压。我们的研究将使用各种基因改造小鼠和技术来了解这种情况发生的机制，希望开发出不会产生负面心血管副作用的未来免疫抑制药物。