DE PEDIATRIC COBRE: EXTRACELLULAR MATRIX REMODELING IN CARDIOVASCULAR DISEASES

DE PEDIATRIC COBRE：心血管疾病中的细胞外基质重塑

基本信息

批准号：
6973099
负责人：
Takeshi Tsuda
金额：
$ 18.61万
依托单位：
ALFRED I. DU PONT HOSP FOR CHILDREN
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-07 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6973099
关键词：
SDS polyacrylamide gel electrophoresis cardiovascular disorder clinical research collagen extracellular matrix extracellular matrix proteins genetically modified animals heart failure hemodynamics histology immunocytochemistry laboratory mouse morphology morphometry pathologic process pediatrics western blottings

项目摘要

Dynamic alterations of the extracellular matrix (ECM) is regarded as an important regulatory step in the development of cardiovascular diseases. This ECM remodeling initiates dysregulation of tissue homeostatsis and eventually induces tissue fibrosis, which results in functional and morphological deterioration of the heart and vessels. ECM remodeling is an important common pathological process in the development of heart failure, vascular restenosis after angioplasty, and pulmonary hypertension, which are all common clinical challenges seen in Pediatrics. Development of tissue fibrosis is a consequence of dysregulation of synthesis and degradation of the ECM. Fibulin-2 is a member of an emerging family of ECM proteins that is up-regulated during morphogenesis of cardiac valves and vessels and that is widely expressed in the vascular basement membrane post-natally. Our preliminary studies with Fibuln-2 deficient mice indicate that Fibulin-2 facilitates collagen deposition and thus myocardial fibrosis after experimental myocardial infarction. Here we propose to investigate regulation of ECM homeostasis in the development of cardiovascular diseases, heart failure and vascular remodeling, using Fibulin-2 deficient mouse model for altered ECM homeostasis. The central hypothesis of this proposal is that Fibulin-2 plays a crucial role in the )athogenesis of heart failure and in the development of vascular remodeling. We have two specific aims. Aim 1 focuses on the role of Fibulin-2 in the development of ventricular remodeling after permanent ischemic injury. For this, we will use both in vivo and in vitro models to determine role of Fibulin-2 in the pathogenesis of ventricular remodeling. Aim 2 focuses the role of Fibulin-2 in the development of vascular remodeling. For this, we will determine the role of Fibulin-2 in vascular remodeling in vivo in experimental models of systemic vascular injury and pulmonary hypertension.

细胞外基质（ECM）的动态改变被认为是心血管疾病发展中的重要调节步骤。这种 ECM 重塑会引发组织稳态失调，最终诱导组织纤维化，从而导致心脏和血管的功能和形态恶化。 ECM重塑是心力衰竭、血管成形术后血管再狭窄和肺动脉高压发展中重要的常见病理过程，这些都是儿科常见的临床挑战。组织纤维化的发展是 ECM 合成和降解失调的结果。 Fibulin-2 是 ECM 蛋白新兴家族的成员，该蛋白在心脏瓣膜和血管的形态发生过程中上调，并在出生后广泛表达于血管基底膜中。我们对 Fibuln-2 缺陷的初步研究小鼠实验表明，Fibulin-2 促进胶原蛋白沉积，从而促进实验性心肌梗塞后的心肌纤维化。在这里，我们建议使用 Fibulin-2 缺陷小鼠模型来改变 ECM 稳态，研究 ECM 稳态在心血管疾病、心力衰竭和血管重塑发展中的调节。该提议的中心假设是 Fibulin-2 在心力衰竭的发生和血管重塑的发展中发挥着至关重要的作用。我们有两个具体目标。目标 1 重点关注 Fibulin-2 在永久性缺血性损伤后心室重塑发展中的作用。为此，我们将使用体内和体外模型来确定 Fibulin-2 在心室重塑发病机制中的作用。目标 2 重点关注 Fibulin-2 在血管重塑发展中的作用。为此，我们将在全身血管损伤和肺动脉高压的实验模型中确定 Fibulin-2 在体内血管重塑中的作用。