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

弹性纤维可以让组织像橡皮筋一样伸展和回缩，在成年人受伤或患有退行性疾病后，弹性纤维不会自然修复或再生。受此类疾病影响的系统称为蛋白水解性疾病，包括皮肤(牛皮癣)、呼吸系统(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细胞过程，这些过程有助于弹性纤维的分解或刺激新纤维的组装和成熟。这些纳米颗粒在影响弹性基质修复方面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(体外)系统中保持存活。这项工作的更广泛影响将是纳米颗粒技术的变革潜力，在全球数百万人遭受心血管疾病困扰的背景下，使强大的现场弹性组织修复成为可能。因此，跨学科项目将为高中生、本科生和研究生提供科学教育和研究培训的机会，通过开发教育模块以及通过各自机构成熟的暑期实习和推广计划。该项目的目标是开发和测试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持续挑战，并用于蛋白质水解性疾病中结构受损组织的功能修复。计划中的方法将(1)在蛋白质水解性损伤组织中确定新的机械调节器，可以通过一氧化氮供体药物来调节，以增加下游弹性形成并抑制蛋白质分解，从而逆转ECM病理生理学；(2)设计并验证一种新型的、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。这些方法将在逆转蛋白水解性疾病腹主动脉瘤的背景下进行测试。研究人员早些时候已经确定了外源性一氧化氮(NO)对弹性基质再生和弹性分解酶的抑制作用，并确定c-Jun-N末端激酶(JNK；一种在蛋白分解障碍中上调的应激激活蛋白激酶)是弹性形成和蛋白分解活性的调节因子。在这个项目中，研究人员将检验一种假设，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供体的给药剂量，从而显著改善刺激弹性基质再生的数量和质量指标。可生物降解的聚合物纳米颗粒经过化学修饰以提供抗蛋白质降解和促进弹性形成的效果，并进一步经组织蛋白酶K(一种弹性蛋白酶)灭活前肽衍生序列的修饰以主动靶向受损的血管壁，将有助于提供可预测的、稳定的和持续的NO供体释放，以实现组织内基质修复。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.