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）： Caveolin-1 (cav-1) 已在许多细胞类型中被发现，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，胰岛素抵抗与高血压之间存在明显的关联。然而，它们之间关联的遗传基础尚未被发现。最近，我们在高血压而非正常血压人群中发现了 cav-1 基因变异与胰岛素抵抗 (IR) 之间的新关联，以及血管对血管紧张素 II 的反应改变。 Cav-1 敲除 (KO) 小鼠也表现出 IR，并改变血管舒张和血管收缩功能；此外，这些血管异常取决于内皮细胞的存在和盐皮质激素受体（MR）的激活状态。因此，基于我们在动物和人类中的平行发现，当前提议的中心假设是 cav-1 基因的遗传变异是高血压和胰岛素抵抗个体血管功能障碍的主要决定因素，并且 cav-1 - 通过它与 MR 的相互作用 - 调节对生理血管反应至关重要的内皮事件。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 位点的遗传变异是否是患有 IR 的高血压患者体内血管功能障碍表型的决定因素。其次，我们将在内皮特异性 cav-1 KO 小鼠体内评估内皮 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增敏（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，本申请开始解决 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 维持血管张力的机制。该提案的结果可能会改善 IR 和高血压患者的预防和差异化治疗方案。

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：
发表时间：
2004
期刊：
影响因子：
0
作者：
Pojoga, Luminita H;Haghiac, Maricela L;Moose, Jana E;Hilderman, Richard H
通讯作者：
Hilderman, Richard H

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

赖氨酸特异性去甲基酶 1 缺陷会以性别特异性方式改变醛固酮合成。

DOI：
发表时间：
2023-01-01
期刊：
影响因子：
0
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