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，使其成为美国第13大死因。主动脉壁的扩大是由弹性蛋白的失效和胶原蛋白的负荷引起的。随着动脉瘤的增大，细胞外基质（ECM）继续变性。我们已经证明，AAA壁的强度也随着它的增大而逐渐降低。当组织的强度低于腔内压力对管壁施加的机械应力时，AAA会破裂。显然，墙的强度和结构完整性在AAA的自然历史中起着重要的作用。为了理解这一自然历史，必须首先阐明墙削弱背后的机制。本研究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，仔细研究AAA壁弱化的两种假设机制。我们的初步工作表明，AAA管壁的应力分布变化很大，存在高应力集中的区域。我们还发现，在AAA内常见的腔内血栓（ILT）会减弱O2向AAA壁的扩散。较厚的ILT层可能导致邻近壁缺氧。我们的假设是，AAA壁的强度是局部应力集中的直接结果，并且在缺氧条件下进一步增强。我们将通过研究从已知应力水平区域和具有厚层和薄层ILT的动脉瘤中新鲜切除的AAA组织来解决这些假设。将评估组织的微观结构以及与壁完整性降解或维持相关的基因表达，如基质金属蛋白酶和ECM前体弹力蛋白和前胶原蛋白。本研究的结果可能会对AAA的临床管理产生直接影响。证明壁强度因壁应力集中或ilt诱导的壁缺氧而降低，将使临床医生能够以更合理的生物物理方式评估AAA。此外，如果这种减弱背后的机制被阐明，可能会开发出抑制或逆转它们的治疗方法，留下一个足够强大的、扩张的主动脉，降低破裂的风险。

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.