Caveolin-1 and vascular dysfunction

Caveolin-1 和血管功能障碍

基本信息

批准号：
8675912
负责人：
Luminita Pojoga
金额：
$ 42.32万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675912
关键词：
Ablation Address Adipocytes Affect Aldosterone Angiotensin II Animal Model Animals Blood Glucose Blood Pressure Blood Vessels CAV1 gene Caveolae Cell membrane Cells Characteristics Data Dietary Sodium Endothelium Enzymes Event Genetic Genetic Markers Genetic Variation Genotype Glucose tolerance test Goals Haplotypes Hereditary Disease Heritability Hormone Receptor Human Hypertension Individual Infusion procedures Insulin Insulin Resistance Integral Membrane Protein Knock-out Knockout Mice Laboratories Lead Leukocytes Link Literature Mediating Metformin Mineralocorticoid Receptor Modeling Mus Pathway interactions Patients Phenotype Physiological Placebos Prevention Prophylactic treatment Proteins Receptor Signaling Renal Blood Flow Research Proposals Resistance profile Resistant Hypertension Role Signal Transduction Single Nucleotide Polymorphism Smooth Muscle Smooth Muscle Myocytes Surrogate Markers Testing Tissues Translational Research Variant Vascular Diseases Vascular Endothelial Cell Vasodilation base brachial artery caveolin 1 cell type cohort eplerenone genetic variant glucose tolerance improved in vivo insulin sensitivity kidney vascular structure knockout animal molecular marker mouse model normotensive novel response salt intake salt sensitive trend vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Caveolin-1 (cav-1) has been identified in many cell types including adipocytes, vascular endothelial cells and smooth muscle cells - where it modulates enzyme and receptor signaling and is involved in both vascular function and insulin sensitivity. Furthermore, there is a clear association between insulin resistance and hypertension; however, the genetic underpinnings of their association are yet to be discovered. Recently, we identified in hypertensive but not normotensive humans, a novel association between cav-1 gene variants and insulin resistance (IR), as well as an altered vascular response to angiotensin II. Cav-1 knockout (KO) mice also displayed IR, and altered vasorelaxation and vasoconstriction; moreover, these vascular abnormalities were dependent on the presence of the endothelium and on the activation state of the mineralocorticoid receptor (MR). Thus, based on our parallel findings in animals and humans, the central hypothesis for the current proposal is that genetic variation in the cav-1 gene is a major determinant of vascular dysfunction in hypertensive and insulin resistant individuals, and that cav-1 - via its interaction with the MR - modulates endothelial events critical for the physiologic vascular response. The overall goal of the present proposal is to expand on our novel preliminary findings in three ways. First, we will determine whether genetic variation at the cav-1 locus is a determinant of vascular dysfunction phenotypes in vivo in hypertensive humans with IR. Second, we will assess in vivo in endothelium-specific cav-1 KO mice, the hypothesis that endothelial cav-1 and MR are critical modulators of vascular function. Third, we will determine in vivo whether insulin sensitization (by metformin) will affect the vascular dysfunction phenotype in the generalized cav-1 KO model. Thus, the current application begins to address the role of cav-1 as one of the genetic underpinnings of vascular dysfunction in IR hypertensive individuals, and explores mechanisms by which endothelial cav-1 maintains vascular tone. The findings resulting from this proposal could lead to improved prevention and differential treatment options for patients with IR and hypertension.

描述（由申请人提供）：在许多细胞类型中已经鉴定出小窝蛋白-1（CAV-1），包括脂肪细胞，血管内皮细胞和平滑肌细胞 - 它调节酶和受体信号传导，并参与血管功能和胰岛素敏感性。此外，胰岛素抵抗和高血压之间存在明显的关联。但是，其关联的遗传基础尚未发现。最近，我们在高血压但不是正常的人类中鉴定出来，这是CAV-1基因变异与胰岛素抵抗（IR）之间的新型关联，以及对血管紧张素II的血管反应改变。 Cav-1敲除（KO）小鼠也显示了IR，并改变了血管征和血管收缩。此外，这些血管异常取决于内皮的存在和矿物皮质激素受体的激活状态（MR）。因此，基于我们在动物和人类中的平行发现，当前建议的中心假设是，Cav -1基因的遗传变异是高血压和抗胰岛素耐药个体血管功能障碍的主要决定因素，而Cav -1通过与MR调节的相互作用对生理学血管响应至关重要。本提案的总体目标是通过三种方式扩展我们新颖的初步发现。首先，我们将确定CAV-1基因座的遗传变异是否是患有IR的高血压人体内血管功能障碍表型的决定因素。其次，我们将评估内皮特异性CAV-1 KO小鼠的体内，这是内皮CAV-1和MR是血管功能的关键调节剂的假设。第三，我们将在体内确定胰岛素敏化（二甲双胍）是否会影响广义CAV-1 KO模型中的血管功能障碍表型。因此，当前的应用开始解决CAV-1作为IR高血压个体血管功能障碍的遗传基础之一的作用，并探索内皮CAV-1保持血管张力的机制。该提案产生的发现可能会导致IR和高血压患者的预防和差异治疗方案的改善。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Determination of ATP impurity in adenine dinucleotides.

腺嘌呤二核苷酸中 ATP 杂质的测定。

DOI：
10.1081/ncn-120030716
发表时间：
2004
期刊：
Nucleosides, nucleotides & nucleic acids
影响因子：
0
作者：
Pojoga,LuminitaH;Haghiac,MaricelaL;Moose,JanaE;Hilderman,RichardH
通讯作者：
Hilderman,RichardH

Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner.

DOI：
10.1530/joe-22-0141
发表时间：
2023-01-01
期刊：
JOURNAL OF ENDOCRINOLOGY
影响因子：
4
作者：
Tan, Yi Jun Desmond;Brooks, Danielle L.;Wong, Kelly Yin Han;Huang, Yuefei;Romero, Jose R.;Williams, Jonathan S.;Pojoga, Luminita H.
通讯作者：
Pojoga, Luminita H.