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：
8492971
负责人：
PAUL J BOOR
金额：
$ 23.18万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492971
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 Property 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 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N-（2-氨基乙基）乙醇胺（AEEA）在全球范围内的生产和使用巨大。人类环境暴露于AEEA，并在各种常见产品中发现AEEA。血管是许多环境毒素的靶标。此外，越来越认识到血管疾病始于童年，可能与产前暴露有关。这个和其他实验室发现，在三个月中，AEEA给怀孕的大鼠（大坝）赋予了新生幼崽的血管病变，称为剖析主动脉瘤或DAA。 DAA是突然的撕裂，或者是胸主动脉肌肉壁的层层。在人类中，DAA会影响青少年至成年初期的人，导致远端血管阻塞，主动脉破裂和猝死。 DAA与几种描述的临床综合症有关，但绝大多数DAA偶尔出现，没有已知的遗传缺陷，并且是高血压是唯一的明显危险因素。这项拟议的研究的长期目标是更好地了解构成动脉解剖的主动脉壁的物理削弱。通过在这种体内模型，血管细胞和自发的高血压大鼠中理解这些机制，可以制定诊断和预防人DAA的策略。要检验的假设是，AEEA的有毒损伤会导致主动脉壁（或培养基）血管平滑肌细胞（VSMC）的胎儿胶原蛋白原纤维化功能障碍。毁灭性的生物物理特性和血管壁的削弱。拟议的研究的理由是，通过了解导致解剖的物理和分子缺陷，可以制定预防或减轻DAA的策略。该假设将通过两个具体目的来解决：首先，主动脉主要结构蛋白（胶原蛋白；弹性蛋白）中的物理缺陷将在体内或体外AEE暴露后定义。这将通过测量用原子力显微镜（AFM）测量主动脉基质和分离分子的物理特性，这是一种测量piconewton分子力的技术。在特定的目标＃2中，将通过以下方式揭示血管解剖和高血压（人类风险因素）的作用（一种危险因素）的作用：这些结合体内的体外，生物物理和分子方法将确定结构/分子毒性作用 AEEA削弱主动脉壁会导致DAA。