Fetal Basis of Dissecting Aortic Aneurysm

主动脉夹层动脉瘤的胎儿基础

• 批准号: 6792928
• 负责人: PAUL J BOOR
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792928
• 关键词: RNA interference; amine oxidoreductase; aorta aneurysm; atomic force microscopy; congenital disorders; elastin; enzyme inhibitors; extracellular matrix; extracellular matrix proteins; gene expression; gene mutation; laboratory rat; mammalian embryology; microarray technology; pathologic process; protein structure function; transfection; vascular smooth muscle

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）是主动脉内侧层的突然撕裂或分裂，通常从其胸段开始，并通过其分支向远端延伸。 DAA 是马凡氏综合征猝死的常见原因，它也作为孤立事件发生，并且与怀孕有关。在最近的实验中，我们发现，通过将定时怀孕的大鼠（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出现典型的 DAA。据我们所知，这是第一个环境诱导的发育 DAA 实验模型。 我们假设发育过程中的 SSAO 抑制会导致关键细胞外基质（结构）蛋白（尤其是弹性蛋白复合物）的细胞生成发生生化、生物物理和遗传畸变，从而导致血管壁减弱。在这个新的实验模型中，我们将重点关注出生前一天的胎鼠，以揭示易患 DAA 的基质环境变化。作为第一个具体目标，将定义主动脉结构成分的生化畸变。将使用令人兴奋的原子力显微镜新技术将单个病理基质分子（例如弹性蛋白复合物）的生物物理特性与正常分子进行比较。通过基因微阵列技术，DAA 之前的基因改变将被揭示。然后，作为第二个具体目标，在从同一胎鼠培养的血管平滑肌细胞中进行机械实验，将探讨基因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。