Collaborative Research: Design and development of a multifunctional nanoplatform for augmented elastic matrix repair

弹性纤维允许组织像橡皮筋一样伸展和弹回，在成年人受伤或患有退行性疾病后不会自然修复或再生。受这种疾病影响的系统称为蛋白水解疾病，包括皮肤（牛皮癣）、呼吸系统（肺气肿）、胃肠系统（肠易激综合征）、自身免疫系统（类风湿性关节炎）和血管系统（动脉瘤）。该项目将使用可生物降解的化学改性聚合物纳米颗粒来研究有助于弹性纤维分解或刺激新纤维组装和成熟的细胞过程。这些纳米颗粒在影响弹性基质修复方面的有效性将在动态/脉动离体（体外）系统中保持活力的结构破坏的血管中进行测试。这项工作的更广泛影响将是纳米颗粒技术在心血管疾病背景下实现强大的现场弹性组织修复的变革潜力，这些疾病困扰着全球数百万人。因此，跨学科项目将通过开发教育模块，并通过在各自机构的完善的暑期实习和推广计划，为高中，本科和研究生提供科学教育和研究培训的机会。该项目的目标是开发和测试一种创新的纳米颗粒平台，旨在增强现场再生弹性组织修复，这是组织工程领域和蛋白水解性疾病中结构受损组织的功能恢复方面的持续挑战。计划的方法将（1）确定蛋白水解损伤组织中的新机制调节剂，其可以用一氧化氮供体药物调节以增加下游弹性生成并抑制蛋白水解以逆转ECM病理生理学，以及（2）设计和验证一种新型的，主动靶向的纳米颗粒平台，以非侵入性方式实现原位组织修复。这些方法将在逆转示例性蛋白水解紊乱、腹主动脉瘤的背景下进行测试。研究者们早先已经确定了外源性一氧化氮（NO）的促弹性基质再生和弹性蛋白分解酶抑制作用，并确定了c-Jun-N-末端激酶（JNK;一种在蛋白水解障碍中上调的应激激活蛋白激酶）作为弹性蛋白生成和蛋白水解活性的调节剂。在这个项目中，研究人员将测试一个假设，即NO通过JNK衰减起作用，这是一个有用的预测指标，以优化NO供体递送剂量，以获得刺激弹性基质再生的数量和定性测量的显着改善。生物可降解的聚合物纳米颗粒经化学修饰以提供抗蛋白水解和促弹性作用，并进一步用组织蛋白酶K修饰（弹性蛋白酶）失活前肽衍生序列，用于主动靶向损伤的血管壁，将用于提供可预测的，稳定的，和持续的NO供体释放，以实现-组织基质修复。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Elastic fibers, which allow tissues to stretch and recoil like rubber bands, are not naturally repaired or regenerated in adults following injury or with degenerative disorders. Systems affected by such disorders, termed proteolytic disorders, include skin (psoriasis), respiratory (emphysema), gastrointestinal (irritable bowel syndrome), auto-immune (rheumatoid arthritis) and vascular (aneurysms). This project will use biodegradable chemically-modified polymer nanoparticles to study cellular processes contributing to the breakdown of elastic fibers or stimulation of new fiber assembly and maturation. The effectiveness of these nanoparticles in influencing elastic matrix repair will be tested in structurally disrupted blood vessels maintained viable in a dynamic/pulsating ex vivo (out of body) system. The broader impact of this work will be the transformative potential of the nanoparticle technology in enabling robust on-site elastic tissue repair in the context of cardiovascular disorders which afflict millions worldwide. Thus interdisciplinary project will provide opportunities for scientific education and research training of high school, undergraduate and graduate students through development of educational modules and through the well-established summer internship and outreach programs at their respective institutions.The goal of this project to develop and test an innovative nanoparticle platform designed to augment on-site regenerative elastic tissue repair, a continuing challenge in the field of tissue engineering, and in functional restoration of tissues structurally compromised in proteolytic diseases. The planned approach will (1) identify new mechanistic regulators in proteolytically-injured tissues that can be modulated with nitric oxide donor drugs to increase downstream elastogenesis and inhibit proteolysis towards reversing ECM pathophysiology and (2) design and validate a novel, actively targeted nanotherapeutic platform to enable on-site tissue repair in a non-invasive manner. These approaches will be tested in the context of reversing an example proteolytic disorder, abdominal aortic aneurysm. The investigators have earlier established the pro-elastic matrix regenerative and elastolytic enzyme-inhibiting effects of exogenous nitric oxide (NO), and identified c-Jun-N-terminal kinase (JNK; a stress-activated protein kinase upregulated in proteolytic disorders) as a regulator of elastogenesis and proteolytic activity. In this project, the investigators will test a hypothesis that NO acts through JNK attenuation, and that this is a useful predictive metric to optimize NO donor delivery doses to obtain significant improvements to the quantity and qualitative measures of stimulated elastic matrix regeneration. Biodegradable polymeric nanoparticles chemically modified to provide anti-proteolytic and pro-elastogenic effects, and further modified with cathepsin K (an elastase)-inactivating propeptide-derived sequences for active targeting to the injured vessel wall, will serve to provide predictable, steady, and sustained NO donor release for effecting in-tissue matrix repair.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.