Bioengineering & Biologic Studies of Aneurysm Weakening

描述(由申请人提供)：每年有15,000名美国人死于腹主动脉破裂，使其成为美国第13大死因。在腹主动脉增大之前，主动脉壁中的弹性蛋白和胶原蛋白的负荷是失败的。随着动脉瘤的扩大，细胞外基质(ECM)继续退化。我们已经证明，随着AAA墙的扩大，其强度也会逐渐降低。当组织的强度降低到腔内压力施加在壁上的机械应力以下时，AAA将破裂。显然，墙体强度和结构完整性在AAA的自然历史中扮演着重要的角色。为了理解这一自然历史，必须首先阐明墙弱化背后的机制。这项拟议的工作的目的是利用最先进的、经过验证的生物工程和生物学方法来研究AAA壁减弱的两个仔细假设的机制。我们的初步工作表明，AAA壁上的应力分布是非常不稳定的，存在应力集中的区域。我们还发现，AAA内常见的管腔内血栓(ILT)可减弱O2向AAA壁上的扩散。较厚的ILT层可能会导致邻近壁的缺氧。我们的假设是，由于局部应力集中，AAA壁的强度在区域内降低，而低氧条件进一步增强了这一点。我们将通过研究新鲜切除的AAA组织来解决这些假设，这些组织来自已知应力水平的区域和具有厚层和薄层ILT的动脉瘤。将评估组织的微结构以及与壁完整性退化或维持相关的基因的表达，如基质金属蛋白酶和细胞外基质前体原弹性蛋白和前胶原。这项研究的结果可能会对AAA的临床治疗产生直接影响。证明室壁应力的局部集中或ILT诱导的室壁缺氧会降低AAA的强度，这将使临床医生能够以更合理的生物物理方式评估AAA。此外，如果阐明了这种减弱背后的机制，可能会开发出抑制或逆转它们的治疗方法，从而使足够坚固、扩张的主动脉破裂的风险降低。

DESCRIPTION (provided by applicant): 15,000 Americans die each year from AAA rupture, making it the 13th leading cause of death in this country. Enlargement of AAA is preceded by failure of the elastin and loading of the collagen in the aortic wall. Extracellular matrix (ECM) degeneration continues as the aneurysm enlarges. We have demonstrated that the strength of the AAA wall is also progressively decreased as it enlarges. The AAA will rupture when the strength of the tissue is reduced below the mechanical stress placed on the wall by the intraluminal pressure. Clearly, wall strength and structural integrity play an important role in the natural history of AAA. To understand this natural history, the mechanisms behind wall weakening must first be elucidated. The purpose of the proposed work is to study 2 carefully hypothesized mechanisms of AAA wall weakening by utilizing state-of-the-art, validated bioengineering and biologic methods. Our preliminary work shows that the stress distribution in the AAA wall is quite variable, with regions of high stress concentrations. We have also shown that the commonly found intraluminal thrombus (ILT) within AAA attenuates diffusion of O2 to the AAA wall. A thick layer of ILT may cause hypoxia of the adjacent wall. Our hypothesis is that the strength of the AAA wall is regionally reduced as a direct result of local stress concentrations and this is further augmented by hypoxic conditions. We will address these hypotheses by studying freshly excised AAA tissue from regions with known stress levels and from aneurysms with thick and thin layers of ILT. The microstructure of the tissue will be assessed along with expression of genes related to either degradation or maintenance of wall integrity, such as matrix metalloproteinases and ECM precursors tropoelastin and procollagen. The results of this study could have an immediate impact on the clinical management of AAA. Demonstration that wall strength is reduced by focal concentrations of wall stress or by ILT-induced mural hypoxia would allow clinicians to evaluate AAA in a more biophysically sound manner. Additionally, if the mechanisms behind this weakening are elucidated, therapies may be developed to inhibit or reverse them, leaving an adequately strong, dilated aorta with a reduced risk of rupture.