NFATc3 in chronic hypoxic pulmonary hypertension

NFATc3 在慢性缺氧性肺动脉高压中的作用

• 批准号: 8197297
• 负责人: Laura V Gonzalez Bosc
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197297
• 关键词: Actins; Address; Affect; Agonist; Altitude; Animal Model; Asthma; Binding; Biology; Blood Vessels; Blood flow; Calcineurin; Calcium; Cause of Death; Cell Differentiation process; Cessation of life; Chronic; Chronic Bronchitis; Collagen Diseases; Complex; Contractile Proteins; Cyclosporine; Cystic Fibrosis; Data; Development; Diagnosis; Disease; Down-Regulation; Endothelin-1; Event; Failure; Family; Fibroblasts; Figs - dietary; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Programming; Genetic Transcription; Genomics; Goals; Heart Diseases; Heart failure; Homeostasis; Hyperplasia; Hypertrophy; Hypoxia; Incidence; Ischemia; Knock-out; Knockout Mice; Lead; Life; Link; Luciferases; Lung; Lung diseases; Maintenance; Measures; Medial; Mediating; Mediator of activation protein; Membrane Potentials; Messenger RNA; Molecular; Molecular Analysis; Molecular Biology; Morbidity - disease rate; Mus; Muscle Contraction; Myosin Heavy Chains; National Heart, Lung, and Blood Institute; Nuclear; Pathology; Patients; Phenotype; Physiological; Physiology; Play; Polycythemia; Potassium; Prevalence; Process; Progressive Disease; Protein Isoforms; Proteins; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Qualifying; Quality of life; Regulation; Regulatory Pathway; Reporter; Reporting; Research; Resistance; Rheumatologic Disorder; Rho-associated kinase; Right Ventricular Hypertrophy; Rodent; Role; Side; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; System; Systems Biology; T-Cell Activation; Testing; Thick; Time; United States; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vasoconstrictor Agents; Ventricular; alpha Actin; arterial remodeling; arteriole; design; extracellular; improved; in vivo; inhibitor/antagonist; knock-down; member; mortality; mouse model; muscle hypertrophy; novel; novel therapeutic intervention; nuclear factors of activated T-cells; outcome forecast; pressure; prevent; primary pulmonary hypertension; promoter; protein expression; pulmonary arterial hypertension; research study; response; sudden cardiac death; tool; transcription factor; transcription factor NF-AT c3; treatment strategy; vasoconstriction; voltage

DESCRIPTION (provided by applicant): Despite the origin of pulmonary arterial hypertension (PAH), pulmonary vascular resistance rises due to pulmonary vasoconstriction, arterial remodeling and polycythemia leading to right heart failure and death. Rodents exposed to chronic hypobaric hypoxia (CH) develop PAH. The complex process of developing PAH is driven, in part, by changes in gene expression. In PAH, smooth muscle intracellular Ca2+ is increased and endothelin 1 (ET-1) expression is up-regulated. Ca2+ regulates pulmonary arterial smooth muscle (PASMC) contraction and is linked to gene transcription through the nuclear factor of activated T cells (NFAT). NFATc3 isoform is specifically implicated in the development of the vasculature and maintenance of smooth muscle differentiate phenotype. The overall goal of this proposal is to determine the role of NFATc3 in the molecular mechanisms underlying the vascular changes associated with CH-PAH. The hypothesis is that CH activates NFATc3 in PASMC to mediate hypertrophy and enhance contractility of pulmonary arteries (PA) contributing to PAH. Specific Aim 1: To determine the role of NFATc3 in CH-induced PASMC hypertrophy and PAH. We will estimate PA pressure, measure mRNA and protein of the hypertrophic markers alpha-actin and myosin heavy chain in PA, NFATc3 binding to 1-actin and myosin heavy chain promoters, and determine structural changes of the pulmonary vasculature on wild type +/- calcineurin/NFAT inhibitor and NFATc3 knockout mice exposed to normoxia and hypobaric CH. Specific Aim 2: To establish the contribution of NFATc3 to CH-induced downregulation of Kv channel expression and increases in pulmonary vasoconstrictor reactivity. We will use the same animal models proposed in aim1 and determine mRNA and protein Kv isoforms; NFATc3 binding to KV 1.5 and 2.1 promoters and association to additional transcriptional regulators; PASMC membrane potential and agonist-induced vasoconstriction in isolated pressurized PA. Specific Aim 3: To determine the mechanisms by which CH increases NFATc3 transcriptional activity in PASMC. We will determine the mediators (ET-1, Ca2+, calcineurin and Rho-kinase) of CH-increased NFAT activity using NFAT-luciferase reporter mice and NFAT-luciferase crossed with NFATc3 KO mice. Findings from the proposed studies will provide novel information about the signaling mechanisms regulating changes in gene transcription in PAH. A better understanding of this mechanisms in PAH will lead to the development of novel therapeutic approaches to prevent and cure this debilitating disease.

描述（由申请人提供）：尽管有肺动脉高压（PAH）的起源，但肺血管阻力由于肺血管收缩、动脉重塑和红细胞增多症而升高，导致右心衰竭和死亡。暴露于慢性低压缺氧 (CH) 的啮齿动物会患上 PAH。形成 PAH 的复杂过程部分是由基因表达的变化驱动的。在 PAH 中，平滑肌细胞内 Ca2+ 增加，内皮素 1 (ET-1) 表达上调。 Ca2+ 调节肺动脉平滑肌 (PASMC) 收缩，并通过活化 T 细胞核因子 (NFAT) 与基因转录相关。 NFATc3 亚型特别涉及脉管系统的发育和平滑肌分化表型的维持。该提案的总体目标是确定 NFATc3 在与 CH-PAH 相关的血管变化的分子机制中的作用。假设 CH 激活 PASMC 中的 NFATc3，介导肥厚并增强肺动脉 (PA) 的收缩性，从而导致 PAH。具体目标 1：确定 NFATc3 在 CH 诱导的 PASMC 肥大和 PAH 中的作用。我们将估计PA压力，测量PA中肥大标记物α-肌动蛋白和肌球蛋白重链的mRNA和蛋白质，NFATc3与1-肌动蛋白和肌球蛋白重链启动子的结合，并确定暴露于常氧和低压CH的野生型+/-钙调神经磷酸酶/NFAT抑制剂和NFATc3敲除小鼠的肺血管系统的结构变化。具体目标 2：确定 NFATc3 对 CH 诱导的 Kv 通道表达下调和肺血管收缩反应性增加的贡献。我们将使用与aim1中提出的相同的动物模型并确定mRNA和蛋白质Kv亚型； NFATc3 与 KV 1.5 和 2.1 启动子结合并与其他转录调节因子关联；隔离加压 PA 中 PASMC 膜电位和激动剂诱导的血管收缩。具体目标 3：确定 CH 增加 PASMC 中 NFATc3 转录活性的机制。我们将使用 NFAT-荧光素酶报告小鼠和与 NFATc3 KO 小鼠杂交的 NFAT-荧光素酶来确定 CH 增加的 NFAT 活性的介质（ET-1、Ca2+、钙调神经磷酸酶和 Rho-激酶）。拟议研究的结果将提供有关调节 PAH 基因转录变化的信号机制的新信息。更好地了解 PAH 的这种机制将有助于开发新的治疗方法来预防和治愈这种使人衰弱的疾病。

项目成果

Aquaporin-2 promoter is synergistically regulated by nitric oxide and nuclear factor of activated T cells.

• DOI: 10.1159/000333066
• 发表时间: 2011-01
• 期刊: Nephron extra
• 作者: Albertoni Borghese MF;Bettini LM;Nitta CH;de Frutos S;Majowicz M;Gonzalez Bosc LV
• 通讯作者: Gonzalez Bosc LV

Nuclear factor of activated T cells is activated in the endothelium of retinal microvessels in diabetic mice.

• DOI: 10.1155/2015/428473
• 发表时间: 2015
• 期刊: Journal of diabetes research
• 影响因子: 4.3
• 作者: Zetterqvist AV;Blanco F;Öhman J;Kotova O;Berglund LM;de Frutos Garcia S;Al-Naemi R;Wigren M;McGuire PG;Gonzalez Bosc LV;Gomez MF
• 通讯作者: Gomez MF

Adrenomedullin expression in the developing human fetal lung.

肾上腺髓质素在发育中的人胎儿肺中的表达。

• DOI: 10.2310/jim.0000000000000020
• 发表时间: 2014
• 期刊: Journal of investigative medicine : the official publication of the American Federation for Clinical Research
• 作者: Ramos,CarlosG;Sun,Xi;Johnson,EricB;Nelson,HaroldE;GonzalezBosc,LauraV
• 通讯作者: GonzalezBosc,LauraV