Ventricular Remodeling in the Adapted Heart

适应心脏的心室重塑

基本信息

批准号：
8231289
负责人：
NILANJANA MAULIK
金额：
$ 40万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231289
关键词：
1-Phosphatidylinositol 3-Kinase Address Adenoviruses Affinity Angiogenesis Inhibitors Annexins Antibodies Apoptosis Apoptotic Area Attention BCL-2 Protein Binding Biological Assay Biological Process Blood Vessels Blood capillaries Blood flow Cardiac Cardiac Myocytes Cardiovascular system Cell Communication Cell Survival Cell physiology Cells Cessation of life Chronic Clinical Collagen Colony-Stimulating Factors Complex Control Groups Coronary Coronary artery DNA Binding DNA Microarray Chip Data Deposition Development Disease Down-Regulation Drug or chemical Tissue Distribution Echocardiography Embryo Endothelial Cells Endothelium Engineering Epidermal Growth Factor Epiregulin Event Failure Family Funding Future Gelshift Analysis Gene Chips Gene Expression Gene Targeting Genes Genetic Goals Grant Growth Factor Health Heart Heat shock proteins Hour Human Hypoxia IkappaB kinase Image Immunohistochemistry In Vitro Infarction Information Networks Injury Investigation Ischemia Ischemic Preconditioning Kidney Knock-out Knockout Mice Lead Ligands Lung Macrophage Colony-Stimulating Factor Malignant Neoplasms Measures Mediating Medical Membrane Microarray Analysis Mitogens Modeling Molecular Molecular Biology Molecular Profiling Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Necrosis Oncogenes Pathway interactions Patients Pattern Phosphorylation Phosphotransferases Physiological Physiology Placental Growth Factor Play Process Proteins Proto-Oncogene Proteins c-akt Protocols documentation Publishing Quality of life RNA Interference Rattus Receptor Protein-Tyrosine Kinases Regulation Research Role SP1 gene SRC gene STAT3 gene Signal Transduction Small Interfering RNA Staining method Stains Stimulus Structure of parenchyma of lung System Systems Development TNFRSF5 gene Techniques Testing Therapeutic Therapeutic Intervention Time Transfection Translating Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Endothelium Vascular Permeabilities Ventricular Function Ventricular Remodeling Western Blotting Work angiogenesis capillary cytokine density design gene repression genetic technology improved in vivo interdisciplinary approach interest member mouse model neovascularization novel novel therapeutics preconditioning protein expression receptor release of sequestered calcium ion into cytoplasm repaired research study response small hairpin RNA survivin therapeutic target transcription factor treatment strategy vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): The central role of vascular endothelial growth factor (VEGF) in angiogenesis health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs in pathological conditions such as cancer and as a pro-angiogenic cytokine for the treatment of ischemic heart disease. VEGF modulates the complex process of angiogenesis and other various aspects of endothelial cell function through either of its two tyrosine kinase receptors, VEGFR1/Flt-1 or VEGFR2/Flk1/KDR via its target protein MK2. In the present proposal we will use Flk-1 , Flt-1 and MK2-/- (MAPKAPKinase2) knockout mice in an attempt to address an important clinical issue to identify potential downstream candidates of VEGF signaling through its receptors that trigger cardioprotective signal during ischemic preconditioning (IP). By Affymetrix gene chip analysis we demonstrated for the first time down regulation of genes (Pellino-1 or Peli-1, Epiregulin and NF?B) after ischemic insult to the Flk-1 mice compared to WT. Studies have identified candidates of the Pellino family as a novel upstream regulator in mediating activation of MAPKAP kinase pathway. PELLINO (Peli) and EPIREGULIN (Ereg) are the newly described molecules downstream of VEGF signaling which might play significant role in myocardial angiogenesis leading to the inhibition of ventricular remodeling. Ereg has angiogenic potential, which may contribute to de novo development of vessels by vasculogenesis or angiogenesis in ischemic/infarcted myocardium. Our long-term goal of this project is to understand the mechanism of VEGF signaling in the ischemic myocardium through newly described molecules Peli-1 and Ereg that we have explored in ischemic myocardium very recently. These are the molecules that may be involved in triggering PI3Kinase/MK2/NF?B pathway involved in angiogenesis. Specific Aim I will determine the involvement of Peli-1, 2 and 3 in IP mediated angiogenesis, Aim II will determine the involvement of MK2 and NF?B in Pellino mediated angiogenesis, Aim III will study the involvement of Ereg in VEGF/PI3-kinase/MK2/NF?B mediated angiogenesis, Aim IV will determine the role and involvement of NF?B in VEGF/Pellino/epiregulin/MK2 mediated myocardial angiogenesis. Genetically engineered NF?B knockout (KO) mice will be used to identify VEGF mediated signaling which may be through NF?B, one of the final target genes related to myocardial angiogenesis. This study will adapt multidisciplinary approach that will consist of various techniques such as modern molecular biology, imaging, gene targeting, siRNA technique and physiology. Collectively, the proposal will contribute to our understanding of the molecular mechanism of VEGF induced angiogenesis and in future may provide novel therapeutic treatment strategies against ischemic heart disease. PUBLIC HEALTH RELEVANCE: To understand VEGF signaling mechanism is a promising medical development in the treatment of ischemia that will likely improve the quality of life in patients who have severe ischemic heart disease.

描述（由申请人提供）：血管内皮生长因子（VEGF）在血管生成健康和疾病中的核心作用使其既可以作为癌症等病理状况下抗血管生成药物的治疗靶点，也可以作为促血管生成细胞因子来治疗癌症。治疗缺血性心脏病。 VEGF 通过其两种酪氨酸激酶受体 VEGFR1/Flt-1 或 VEGFR2/Flk1/KDR（通过其靶蛋白 MK2）调节血管生成和内皮细胞功能的其他各个方面的复杂过程。在目前的提案中，我们将使用 Flk-1 、 Flt-1 和 MK2-/- (MAPKAPKinase2) 敲除小鼠，试图解决一个重要的临床问题，通过其受体识别 VEGF 信号传导的潜在下游候选者，这些受体在缺血期间触发心脏保护信号预处理（IP）。通过 Affymetrix 基因芯片分析，我们首次证明与 WT 相比，Flk-1 小鼠缺血损伤后基因（Pellino-1 或 Peli-1、Epiregulin 和 NF?B）下调。研究已确定 Pellino 家族的候选者是介导 MAPKAP 激酶途径激活的新型上游调节因子。 PELLINO (Peli) 和 EPIREGULIN (Ereg) 是新近描述的 VEGF 信号下游分子，可能在心肌血管生成中发挥重要作用，从而抑制心室重塑。 Ereg 具有血管生成潜力，可能有助于通过血管发生或缺血/梗塞心肌中的血管生成来促进血管的从头发育。我们这个项目的长期目标是通过我们最近在缺血心肌中探索的新描述的分子 Peli-1 和 Ereg 来了解缺血心肌中 VEGF 信号传导的机制。这些分子可能参与触发参与血管生成的 PI3Kinase/MK2/NF?B 途径。具体目标 I 将确定 Peli-1、2 和 3 在 IP 介导的血管生成中的参与，目标 II 将确定 MK2 和 NF?B 在 Pellino 介导的血管生成中的参与，目标 III 将研究 Ereg 在 VEGF/PI3- 中的参与激酶/MK2/NF?B 介导的血管生成，Aim IV 将确定 NF?B 在 VEGF/Pellino/epiregulin/MK2 介导的心肌中的作用和参与血管生成。基因工程 NFκB 敲除 (KO) 小鼠将用于鉴定 VEGF 介导的信号传导，该信号可能通过 NFκB 介导，NFκB 是与心肌血管生成相关的最终靶基因之一。这项研究将采用多学科方法，包括现代分子生物学、成像、基因靶向、siRNA 技术和生理学等多种技术。总的来说，该提案将有助于我们了解 VEGF 诱导血管生成的分子机制，并在未来可能为缺血性心脏病提供新的治疗策略。公众健康相关性：了解 VEGF 信号传导机制是治疗缺血的一项有前途的医学发展，可能会改善患有严重缺血性心脏病的患者的生活质量。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction.

DOI：
10.1371/journal.pone.0034790
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Adluri RS;Thirunavukkarasu M;Zhan L;Dunna NR;Akita Y;Selvaraju V;Otani H;Sanchez JA;Ho YS;Maulik N
通讯作者：
Maulik N