Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm

项目摘要/摘要 腹主动脉瘤(Aaa)是一种由于腹主动脉弹性纤维完整性丧失而导致的主动脉增大。 血管壁。随着血管的增大，危及生命的破裂的风险也会增加。一旦直径达到 阈值为5.5厘米，假设破裂风险大于手术干预的风险，这是目前唯一 批准用于治疗AAA的方法。然而，阈值以下的AAA仍有约13%的时间破裂， 表明需要进行临界值前治疗以减缓或阻止动脉瘤的增长。提供可再生的 抑制弹性纤维的降解并增加弹性形成和胶原合成的治疗方法可能 机械地稳定血管，减缓动脉瘤的进展。 对于避免全身副作用来说，对动脉瘤部位进行局部控制的治疗将是理想的。一个 基于细胞但无细胞的处理也将提供与含有细胞的处理相似的再生效果 治疗，但将避免施加在含有细胞的治疗上的严格监管障碍。具体而言 提到脂肪基质细胞(ASCs)，使用它们的细胞外小泡(EV)也可以避免植入 以及细胞本身的分化，同时仍发挥其再生作用。同样重要的是， 持续释放治疗，以在更长的一段时间内对AAA发挥作用。 这项提议旨在开发电动汽车的磁铁可定位控制释放系统。这个系统将是 使用种植在3D纤维蛋白凝胶结构中的血管平滑肌细胞(VSMCs)进行验证，特别是观察 所交付的EV如何调节基质相关基因的表达以及弹性蛋白和胶原的沉积。为了测试 这些电动汽车如何通过外周给药到达AAA中的内侧VSMCs，电动汽车将是 评估进入瘤样猪主动脉的情况。基于这些实验结果，提出了一种 将开发计算传输模型来预测EVS进入动脉瘤组织的移动。这个 该项目的结果可作为小型AAA的新的再生治疗的基础，并提供 一种计算工具，用于模拟外部治疗如何到达内侧VSMC。通过这个项目， 申请者将学习研究(包括实验和计算)、沟通、教学技巧。 作为科学和临床知识，通过她在华盛顿大学的学术、研究和临床导师 匹兹堡。

Project Summary/Abstract Abdominal aortic aneurysm (AAA) is an enlargement of the aorta caused by loss of elastic fiber integrity in the vascular wall. As the vessel grows, the risk of life-threatening rupture increases. Once the diameter reaches the threshold of 5.5 cm, the risk of rupture is assumed to outweigh the risk of surgical intervention, the only current method approved for treating AAAs. However, sub-threshold AAAs still rupture about 13% of the time, demonstrating the need for a pre-threshold treatment to slow or halt aneurysm growth. Providing a regenerative treatment that inhibits the degradation of elastic fibers and increases elastogenesis and collagen synthesis may stabilize the vessel mechanically and slow aneurysm progression. Local controlled delivery of a treatment to the aneurysm site would be ideal for avoiding systemic side effects. A cell-based yet cell-free treatment would also provide similar regenerative effects to that of a cell-containing treatment but would avoid the intense regulatory hurdles imposed on cell-containing therapies. In specific reference to adipose stromal cells (ASCs), using their extracellular vesicles (EVs) can also avoid engraftment and differentiation of the cells themselves while still exerting their regenerative effects. It is also important to have sustained release of the treatment to exert its effects on the AAA for a longer period of time. This proposal serves to develop a magnet-localizable controlled release system of EVs. This system will be validated using vascular smooth muscle cells (VSMCs) seeded in 3D fibrin gel constructs, specifically looking at how the delivered EVs modulate matrix-related gene expression and elastin and collagen deposition. To test how these EVs could reach the medial VSMCs in an AAA through adventitial administration, EVs will be evaluated for movement into aneurysmal-like porcine aortas. Based on these experimental results, a computational transport model will be developed to predict movements of EVs into aneurysmal tissue. The results of this project could serve as the foundation for a novel regenerative treatment of small AAAs and provide a computational tool to model how external treatments can reach medial VSMCs. Through this project, the applicant will learn research (both experimentally and computationally), communication, teaching skills as well as scientific and clinical knowledge through her academic, research, and clinical mentors at the University of Pittsburgh.