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

弹性纤维可以使组织像橡皮筋一样伸展和收缩，在成人受伤或退行性疾病后不能自然修复或再生。受这些疾病影响的系统，被称为蛋白质溶解性疾病，包括皮肤（牛皮癣）、呼吸（肺气肿）、胃肠道（肠易激综合征）、自身免疫（类风湿性关节炎）和血管（动脉瘤）。该项目将使用可生物降解的化学修饰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。这些纳米颗粒影响弹性基质修复的有效性将在结构破坏的血管中进行测试，这些血管在动态/脉动的体外系统中保持活力。这项工作的更广泛的影响将是纳米颗粒技术的变革潜力，在全球数百万人患有心血管疾病的情况下，它可以实现强大的现场弹性组织修复。因此，跨学科项目将通过开发教育模块和在各自机构建立良好的暑期实习和外展计划，为高中、本科生和研究生的科学教育和研究培训提供机会。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，这是组织工程领域的一个持续挑战，也是蛋白质水解性疾病中结构受损组织的功能恢复。计划中的方法将(1)在蛋白水解损伤组织中确定新的机制调节因子，可以用一氧化氮供体药物调节，以增加下游弹性形成和抑制蛋白水解，从而逆转ECM病理生理；(2)设计并验证一种新的、主动靶向的纳米治疗平台，以非侵入性方式实现现场组织修复。这些方法将在逆转一例蛋白溶解性疾病腹主动脉瘤的背景下进行测试。研究人员早前已经证实了外源性一氧化氮（NO）对促弹性基质再生和弹性分解酶的抑制作用，并确定了c- jun - n末端激酶（JNK，一种在蛋白水解紊乱中上调的应激激活蛋白激酶）是弹性发生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，可以优化NO供体给药剂量，从而显著提高受激弹性基质再生的数量和质量。生物可降解的聚合物纳米颗粒经过化学修饰，具有抗蛋白水解和促弹性作用，并进一步用组织蛋白酶K（一种弹性酶）失活的前肽衍生序列修饰，用于主动靶向受损血管壁，将有助于提供可预测的、稳定的、持续的NO供体释放，从而影响组织内基质修复。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.