Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm

细胞外囊泡递送系统治疗腹主动脉瘤

• 批准号: 10751123
• 负责人: Ande Xiaojie Marini
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751123
• 关键词: 3-Dimensional; Abdominal Aortic Aneurysm; Address; Adipose tissue; Affect; American; Aneurysm; Aorta; Blood Vessels; Cell Differentiation process; Cell secretion; Cells; Chronic; Clinical; Collagen; Communication; Computer Models; Degenerative Disorder; Deposition; Diameter; Diffuse; Educational process of instructing; Elastic Fiber; Elastin; Encapsulated; Engraftment; Environment; Evaluation; Exposure to; Extracellular Matrix; Family suidae; Fibrin; Flow Cytometry; Foundations; Gel; Gene Expression; Growth; In Vitro; Intervention; Iron; Knowledge; Label; Learning; Life; Magnetism; Mechanics; Medial; Mentors; Methods; Modeling; Monitor; Movement; Operative Surgical Procedures; Patients; Penetration; Physiological; Property; Proteins; Research; Risk; Rupture; Side; Silk; Site; Smooth Muscle Myocytes; Stromal Cells; Structural Protein; System; Technology; Testing; Therapeutic; Thrombus; Time; Tissues; Tunica Adventitia; Universities; Vascular Smooth Muscle; Woman; aqueous; computerized tools; controlled release; ex vivo perfusion; experimental study; extracellular vesicles; hemodynamics; high risk; innovation; men; mouse model; nanoparticle; novel; particle; preservation; pressure; regenerative; regenerative treatment; repaired; restoration; side effect; skills; standard of care; stem cells; surgical risk; uptake; vesicle transport; vesicular release

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.

项目摘要/摘要 腹主动脉瘤（AAA）是由弹性纤维完整性丧失引起的主动脉的扩大 血管壁。随着血管的生长，威胁生命的破裂风险增加。一旦直径到达 阈值为5.5厘米，假定破裂的风险超过了手术干预的风险，这是唯一的当前 批准治疗AAA的方法。但是，阈值AAAS仍大约有13％的时间破裂， 证明需要进行阈值前治疗以减慢或停止动脉瘤的生长。提供再生 抑制弹性纤维降解并增加弹性发生和胶原蛋白合成的处理可能 机械稳定血管并缓慢动脉瘤进展。 局部受控到达动脉瘤部位的治疗将是避免系统性副作用的理想选择。一个 基于细胞的但无细胞的治疗也将提供与含细胞的再生作用 治疗，但会避免对含细胞的疗法施加的严重调节障碍。具体 参考脂肪基质细胞（ASC），使用其细胞外囊泡（EV）也可以避免植入 和细胞本身的区分，同时仍能发挥其再生作用。这也很重要 持续释放治疗，以在更长的时间内对AAA发挥影响。 该提案有助于开发电动汽车的可磁性控制释放系统。这个系统将是 使用3D纤维蛋白凝胶构建体的血管平滑肌细胞（VSMC）验证 传递的EV如何调节基质相关的基因表达以及弹性蛋白和胶原蛋白沉积。测试 这些电动汽车如何通过Advenditial Adminissmation在AAA中到达内侧VSMC，EV将是 评估运动进入动脉瘤样猪主动脉。基于这些实验结果 将开发计算传输模型来预测电动汽车向动脉瘤组织的运动。这 该项目的结果可以作为对小型AAA的新再生治疗的基础，并提供 一种计算工具，用于建模外部处理如何达到内侧VSMC。通过这个项目， 申请人将学习研究（通过实验和计算），沟通，教学技能 通过她的学术，研究和临床导师作为科学和临床知识 匹兹堡。