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AAA破裂，使其成为该国第13大死亡原因。AAA的扩张之前是弹性蛋白的失效和主动脉壁中胶原的负载。随着动脉瘤的扩大，细胞外基质（ECM）的退化继续。我们已经证明，AAA壁的强度也随着其扩大而逐渐降低。当组织的强度降低到低于腔内压力施加在壁上的机械应力时，AAA将破裂。显然，壁强度和结构完整性在AAA的自然历史中起着重要作用。为了理解这一自然过程，必须首先阐明壁弱化背后的机制。拟议工作的目的是通过利用最先进的、经验证的生物工程和生物学方法研究AAA壁弱化的2种仔细假设的机制。我们的初步工作表明，在AAA壁的应力分布是相当可变的，与高应力集中区。我们还发现，AAA内常见的腔内血栓（ILT）减弱了O2向AAA壁的扩散。厚的ILT层可引起相邻壁缺氧。我们的假设是，AAA壁的强度是区域性降低的局部应力集中的直接结果，这是进一步增强缺氧条件。我们将通过研究来自已知应力水平区域和具有厚层和薄层ILT的动脉瘤的新鲜切除AAA组织来解决这些假设。将沿着评估组织的微观结构以及与壁完整性的降解或维持相关的基因的表达，例如基质金属蛋白酶和ECM前体原弹性蛋白和原胶原。本研究的结果可能对AAA的临床管理产生直接影响。室壁应力的局灶性集中或ILT诱导的室壁缺氧会降低室壁强度，这一证明将使临床医生能够以更符合生物病理学的方式评价AAA。此外，如果这种弱化背后的机制得到阐明，可以开发治疗方法来抑制或逆转它们，留下足够强大的扩张主动脉，降低破裂风险。

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.