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

合作研究：设计和开发用于增强弹性基质修复的多功能纳米平台

• 批准号: 1926939
• 负责人: Anand Ramamurthi
• 金额: $ 30万
• 依托单位: Cleveland Clinic Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1926939&HistoricalAwards=false
• 关键词: Collaborative; Research; Design; development; multifunctional

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.

弹性纤维可以让组织像橡皮筋一样伸展和回缩，但在成人受伤或患有退行性疾病后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改性聚合物纳米粒子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。这些纳米粒子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，该血管在动态/脉动离体（体外）系统中保持活力。这项工作的更广泛影响将是纳米粒子技术的变革潜力，在困扰全球数百万人的心血管疾病的背景下实现强大的现场弹性组织修复。因此，跨学科项目将通过教育模块的开发以及各自机构完善的暑期实习和外展计划，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。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，这是组织工程和组织功能恢复领域的持续挑战 蛋白水解疾病中结构受损。计划的方法将（1）在蛋白水解损伤的组织中识别新的机械调节剂，这些调节剂可以用一氧化氮供体药物进行调节，以增加下游弹性生成并抑制蛋白水解，从而逆转 ECM 病理生理学；（2）设计和验证一种新颖的、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障碍（腹主动脉瘤）的背景下进行测试。研究人员较早地确定了外源性一氧化氮 (NO) 的促弹性基质再生和弹性蛋白水解酶抑制作用，并确定 c-Jun-N 末端激酶（JNK；一种在蛋白水解疾病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。在该项目中，研究人员将测试 NO 通过 JNK 衰减发挥作用的假设，这是一个有用的预测指标，可优化 NO 供体输送剂量，从而显着改善刺激弹性基质再生的数量和定性测量。可生物降解的聚合物纳米颗粒经过化学修饰，可提供抗蛋白水解和促弹性作用，并进一步用组织蛋白酶 K（一种弹性蛋白酶）灭活前肽衍生序列进行修饰，以主动靶向受伤的血管壁，将有助于提供可预测、稳定和持续的 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，并具有 通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。