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.
