Fetal Basis of Dissecting Aortic Aneurysm

主动脉夹层动脉瘤的胎儿基础

基本信息

批准号：
7036519
负责人：
PAUL J BOOR
金额：
$ 14.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
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：
2004-05-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7036519
关键词：
RNA interference amine oxidoreductase aorta aneurysm atomic force microscopy congenital disorders elastin enzyme inhibitors extracellular matrix proteins gene expression gene mutation laboratory rat mammalian embryology microarray technology pathologic process protein structure function transfection vascular smooth muscle

项目摘要

DESCRIPTION (provided by applicant): Dissecting aortic aneurysm (DAA) is the sudden tearing or splitting of the medial layers of the aorta, usually beginning in its thoracic portion, and extending distally through its branches. A frequent cause of sudden death in Marfan's syndrome, DAA also occurs as an isolated event, and is associated with pregnancy. In recent experiments, we found that by exposing timed-pregnant rats (on days 14-21 of gestation) to nontoxic doses of semicarbazide, an inhibitor of the vascular enzyme semicarbazide-sensitive amine oxidase (SSAO), newborn rats develop classic DAA immediately after birth. To our knowledge, this is the first experimental model of environmentally induced, developmental DAA. We hypothesize that SSAO-inhibition during development results in biochemical, biophysical, and genetic aberrations in the cellular production of critical extracellular matriceal (structural) proteins, especially the elastin-complex, with resultant weakening of the vascular wall. In this new experimental model, we will focus on the fetal rat, the day before birth, to uncover the changes in matrix milieu that predispose to DAA. As a first Specific Aim, the biochemical aberrations in aortic structural components will be defined. Biophysical properties of single pathologic matrix molecules (e.g., elastin-complex) will be compared to normal using the exciting new technique of atomic-force-microscopy. With gene microarray techniques, genetic alterations that precede DAA will be revealed. Then, as a second Specific Aim, mechanistic experiments in vascular smooth muscle cells cultured from the same fetal rats will probe how genetic alterations drive the changes in aortic extracellular matrix milieu to result in vascular weakening, and dissection.

描述（由申请人提供）：解剖主动脉瘤（DAA）是主动脉内侧层的突然撕裂或分裂，通常始于其胸部部分，并通过其分支远端延伸。 DAA经常出现Marfan综合征突然死亡的原因，也是一个孤立的事件，与怀孕有关。在最近的实验中，我们发现，通过将定时怀孕的大鼠（在妊娠的第14-21天）暴露于无毒剂量的半北极氮，这是血管酶半氨基胺敏感胺氧化酶（SSAO）的抑制剂，新生大鼠在出生后立即出现经典的DAA。据我们所知，这是环境引起的开发DAA的第一个实验模型。我们假设在发育过程中的SSAO抑制作用会导致临界细胞外基质（结构）蛋白的细胞产生生物化学，生物物理和遗传像差，尤其是弹性蛋白 - 复合物，导致血管壁的弱化。在这个新的实验模型中，我们将重点关注胎儿大鼠出生的前一天，以揭示易于DAA的基质环境的变化。作为第一个特定目的，将定义主动脉结构成分中的生化畸变。使用原子能微观镜的激动人心的新技术将单个病理基质分子（例如弹性蛋白复合物）的生物物理特性（例如弹性蛋白复合体）进行比较。使用基因微阵列技术，将揭示在DAA之前的遗传改变。然后，作为第二个特定目的，从同一胎儿大鼠培养的血管平滑肌细胞中的机械实验将探测遗传改变如何驱动主动脉外基质基质环境的变化，从而导致血管弱和解剖。