Atomic Force Microscopic Studies of Dissecting Aneurysm

夹层动脉瘤的原子力显微镜研究

基本信息

批准号：
8668960
负责人：
PAUL J BOOR
金额：
$ 19.17万
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：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668960
关键词：
Abdominal Aortic Aneurysm Acute Address Affect Aging Amines Aneurysm Aorta Aortic Rupture Arteries Atomic Force Microscopy Attention Attenuated Biochemical Birth Blood Vessels Brain Cells Characteristics Chemicals Childhood Clinical Collagen Cosmetics Data Defect Diagnosis Disease Dissecting Aneurysm Dissecting aortic aneurysm Dissection Distal Elastin Elderly Environment Environmental Exposure Environmental Health Ethanolamines Exposure to Goals Head and neck structure Heart Household Products Human Hypertension In Vitro Inbred SHR Rats Individual Industry Injury Laboratories Lead Lesion Limb structure Measures Medial Microscopic Modeling Molecular Muscle Mutation Newborn Infant Organ Outcome Pathogenesis Pathologic Processes Persons Pregnancy Pregnant Women Prevention Production Proteins Public Health Publishing Rattus Research Residual state Risk Factors Role Rupture Smooth Muscle Myocytes Structural Protein Sudden Death Syndrome Techniques Teenagers Testing Third Pregnancy Trimester Thoracic aorta Toxic Environmental Substances Toxic effect Toxin Vascular Diseases biophysical properties emerging adult experience fetal fibrillogenesis genetic manipulation in vivo in vivo Model innovation offspring physical property postnatal pregnant prenatal prenatal exposure prevent public health relevance pup social stigma

项目摘要

DESCRIPTION (provided by applicant): The industrial chemical N-(2-aminoethyl) ethanolamine (AEEA) has enormous worldwide production and use. Human environmental exposures to AEEA occur, and AEEA is found in a variety of common products. Blood vessels are the target of many environmental toxins. Furthermore, it is becoming increasingly recognized that vascular disorders begin in childhood, and may be related to prenatal exposure. This and other laboratories have found that AEEA, given to pregnant rats (dams) during their third trimester, results in a vascular lesion in newborn pups known as dissecting aortic aneurysm, or DAA. DAA is the sudden tearing, or splitting of the layers of the muscular wall of the thoracic aorta. In humans, DAA affects those in the teen years to early adulthood, resulting in occlusion of distal vessels, aortic rupture, and sudden death. DAA is associated with several well-described clinical syndromes, but the vast majority of DAAs occur sporadically, without known genetic defects, and with hypertension as the only clear-cut risk factor. The long-term goal of this proposed research is to better understand the physical weakening of the aortic wall that underlies arterial dissection; by understanding these mechanisms in this in vivo model, in vascular cells, and in spontaneously hypertensive rats, strategies for diagnosis and prevention of human DAA can be devised. The hypothesis to be tested is that AEEA's toxic insult causes damaged, dysfunctional fetal collagen fibrillogenesis by vascular smooth muscle cells (VSMCs) of the aortic wall (or media). Deranged biophysical properties and weakening of the blood vessel wall result. The rationale for the proposed studies is that by understanding the physical and molecular defects that lead to dissection, strategies to prevent or attenuate DAA can be devised. The hypothesis will be addressed by two Specific Aims: First, physical defects in the aorta's major structural proteins (collagen; elastin) will be defined after in vivo or in vitro AEE exposure. This will be accomplished by measuring physical characteristics of aortic matrix and isolated molecules with atomic force microscopy (AFM), a technique that measures piconewton molecular forces. In Specific Aim #2, mechanisms underlying vascular dissection and the role of hypertension (a risk factor in humans) will be revealed by: a) characterizing defects from matrix produced by isolated VSMCs through biochemical and molecular techniques, and b) defining prenatal AEEA effects in control and spontaneously hypertensive rats. These combined in vivo, in vitro, biophysical and molecular approaches will identify the structural/molecular toxic effects of AEEA that weaken the aortic wall to result in DAA.

描述（由申请人提供）：工业化学品 N-(2-氨基乙基)乙醇胺 (AEEA) 在全球范围内有着巨大的生产和使用量。人类环境会暴露于 AEEA，并且 AEEA 存在于各种常见产品中。血管是许多环境毒素的目标。此外，人们越来越认识到血管疾病始于儿童期，并且可能与产前暴露有关。该实验室和其他实验室发现，在妊娠晚期给怀孕大鼠（母鼠）注射 AEEA 会导致新生幼鼠出现血管病变，称为夹层主动脉瘤（DAA）。 DAA 是胸主动脉肌肉壁层的突然撕裂或分裂。在人类中，DAA 会影响青少年至成年早期的人，导致远端血管闭塞、主动脉破裂和猝死。 DAA 与几种已明确描述的临床综合征相关，但绝大多数 DAA 是零星发生的，没有已知的遗传缺陷，并且高血压是唯一明确的危险因素。这项研究的长期目标是更好地了解动脉夹层背后的主动脉壁的物理弱化；通过了解体内模型、血管细胞和自发性高血压大鼠的这些机制，可以设计诊断和预防人类 DAA 的策略。要测试的假设是，AEEA 的毒性损伤会导致主动脉壁（或中膜）的血管平滑肌细胞 (VSMC) 受损、功能失调的胎儿胶原纤维生成。导致生物物理特性紊乱和血管壁变弱。拟议研究的基本原理是，通过了解导致解剖的物理和分子缺陷，可以设计出预防或减弱 DAA 的策略。该假设将通过两个具体目标来解决：首先，在体内或体外 AEE 暴露后，将确定主动脉主要结构蛋白（胶原蛋白；弹性蛋白）的物理缺陷。这将通过使用原子力显微镜（AFM）测量主动脉基质和孤立分子的物理特性来实现，原子力显微镜是一种测量皮牛顿分子力的技术。在具体目标 #2 中，血管解剖的潜在机制和高血压（人类的危险因素）的作用将通过以下方式揭示：a) 通过生化和分子技术表征分离的 VSMC 产生的基质缺陷，b) 定义产前 AEEA 效应在对照和自发性高血压大鼠中。这些体内、体外、生物物理和分子方法相结合将确定结构/分子毒性作用 AEEA 削弱主动脉壁，导致 DAA。