HIMF/FIZZ1 IN PULMONARY HYPERTENSION/RIGHT HEART FAILURE

肺动脉高压/右心衰竭中的 HIMF/FIZZ1

基本信息

批准号：
7231193
负责人：
Roger A Johns
金额：
$ 46.26万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7231193
关键词：
Angiotensins Animal Model Binding Blood Vessels Candidate Disease Gene Cardiac Myocytes Cell Cycle Cell Proliferation Cessation of life Chronic Clinical Complex Dependovirus Development Disease Endothelial Cells Endothelin Etiology Event Generations Genes Genomics Growth Growth Factor Heart Heart Hypertrophy Heart failure Human Hyperplasia Hypertrophy Hypoxia Inflammation Inflammatory Interleukin-2 Lesion Lung Mediating Mitogenic Factor Receptors Modeling Monocrotaline Mus Names PCNA gene Patients Physiological Post-Translational Protein Processing Process Production Property Proteomics Pulmonary Hypertension Pulmonary vessels Rattus Reactive Oxygen Species Receptor Inhibition Recombinants Recruitment Activity Right Ventricular Hypertrophy Right ventricular structure Role Scleroderma Serotonin Signal Pathway Simvastatin Smooth Muscle Myocytes Vascular Endothelial Growth Factors Vascular remodeling Ventricular Remodeling analog base cell motility chemokine cytokine in vivo macrophage monocyte novel prevent pulmonary arterial hypertension research study sildenafil vasculogenesis vasoconstriction

项目摘要

Pulmonary hypertension, a disease of multiple etiologies but poorly understood mechanisms, eventually leads to right ventricular hypertrophy, heart failure and often death. Recently, in a hypoxia-induced model of pulmonary hypertension, we found a gene that was highly upregulated, which we named hypoxia- induced mitogenic factor (HIMF). We found HIMF to be expressed in the remodeling PCNA positive pulmonary vessels and demonstrated that recombinant HIMF had mitogenic, angiogenic, vasoconstrictive and chemokine-like properties. HIMF/FIZZ1 is thus a novel candidate gene involved in the complex interplay between pulmonary vascular and right ventricular remodeling, a central focus of this SCCOR application. We hypothesize that HIMF is a polyvalent cytokine, which mediates critical lung cellular events in hypertensive pulmonary vascular remodeling, and is involved in the transition of adaptive to maladaptive right ventricle in pulmonary hypertension. Specific Aim #1 will examine the role of HIMF/FIZZ1 in the mechanism of pulmonary hypertension in animal models that emphasize hypoxia-related remodeling (chronic hypoxia exposure), inflammation (monocrotaline) and abnormal vessel growth (plexiform lesions and vascular remodeling associated with combined chronic hypoxia and VEGF2 receptor inhibition). Specific Aim #2 will use genomic, proteomic, and physiologic/pharmacologic approaches to examine HIMF effect on components of known downstream HIMF signaling pathways related to PAH and vascular remodeling including inflammation, growth factors/cell cycle activation, angio/vasculogenesis and reactive oxygen species generation in lung and heart. Specific Aim #3 will identify the HIMF receptor(s) and/or binding partners in lung and heart utilizing proteomics to identify its interactome network and post- translational modifications (PTMs) in lung and heart during the development of PAH. Specific Aim #4 will investigate the role and mechanism of HIMF inhibition in the protective and reversal actions of simvastatin and sildenafil on pulmonary vascular remodeling and right ventricular remodeling in models of PAH.

肺动脉高压是一种有多种病因但对其机制知之甚少的疾病，最终导致右心室肥厚、心力衰竭，甚至死亡。最近，在缺氧诱导的模型中在肺动脉高压中，我们发现了一个高度上调的基因，我们将其命名为缺氧- 诱导有丝分裂因子（HIMF）。我们发现HIMF在重塑PCNA阳性中表达并证明重组 HIMF 具有促有丝分裂、血管生成、血管收缩作用和趋化因子样特性。因此，HIMF/FIZZ1 是参与该复合体的一个新的候选基因。肺血管和右心室重塑之间的相互作用，是本次 SCCOR 的中心焦点应用。我们假设 HIMF 是一种多价细胞因子，介导关键的肺细胞事件高血压肺血管重塑，并参与适应性向适应不良的转变右心室肺动脉高压。具体目标 #1 将研究 HIMF/FIZZ1 在强调缺氧相关重塑的动物模型中肺动脉高压的机制（慢性缺氧暴露）、炎症（野百合碱）和异常血管生长（丛状病变）以及与慢性缺氧和 VEGF2 受体抑制联合相关的血管重塑）。具体目标#2将使用基因组学、蛋白质组学和生理学/药理学方法来检查 HIMF 对与 PAH 和血管相关的已知下游 HIMF 信号通路成分的影响重塑，包括炎症、生长因子/细胞周期激活、血管/血管生成和反应性肺和心脏中产生氧气。具体目标 #3 将识别 HIMF 受体和/或肺和心脏中的结合伙伴利用蛋白质组学来识别其相互作用组网络和后 PAH 发展过程中肺和心脏的翻译修饰 (PTM)。具体目标 #4 将研究HIMF抑制在辛伐他汀保护和逆转作用中的作用和机制西地那非对 PAH 模型中肺血管重构和右心室重构的影响。