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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）：夹层主动脉瘤（DAA）是主动脉中层的突然撕裂或分裂，通常始于其胸部，并通过其分支向远端延伸。DAA是马凡氏综合征中猝死的常见原因，也作为孤立事件发生，并与妊娠相关。在最近的实验中，我们发现，通过将定时妊娠大鼠（妊娠第14-21天）暴露于无毒剂量的氨基脲（一种血管酶氨基脲敏感胺氧化酶（SSAO）的抑制剂），新生大鼠在出生后立即发生经典的DAA。据我们所知，这是第一个实验模型的环境诱导，发育DAA。我们推测，SSAO抑制在发展过程中的结果在生化，生物物理，和遗传畸变的细胞生产的关键细胞外matriceal（结构）蛋白，特别是弹性蛋白复合物，从而削弱血管壁。在这个新的实验模型中，我们将重点放在出生前一天的胎鼠上，以揭示易患DAA的基质环境的变化。作为第一个特定目标，将定义主动脉结构组件中的生化畸变。单个病理基质分子的生物物理性质（例如，弹性蛋白复合物）将使用令人兴奋的原子力显微镜新技术与正常进行比较。利用基因微阵列技术，DAA之前的遗传改变将被揭示。然后，作为第二个特定目标，在从相同胎鼠培养的血管平滑肌细胞中进行的机制实验将探索遗传改变如何驱动主动脉细胞外基质环境的变化，从而导致血管弱化和夹层。