| NSF Org: |
CBET Division of Chemical, Bioengineering, Environmental, and Transport Systems |
| Recipient: |
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| Initial Amendment Date: | June 1, 2015 |
| Latest Amendment Date: | June 1, 2015 |
| Award Number: | 1508642 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Aleksandr Simonian
asimonia@nsf.gov (703)292-2191 CBET Division of Chemical, Bioengineering, Environmental, and Transport Systems ENG Directorate for Engineering |
| Start Date: | July 1, 2015 |
| End Date: | June 30, 2019 (Estimated) |
| Total Intended Award Amount: | $300,000.00 |
| Total Awarded Amount to Date: | $300,000.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
9500 EUCLID AVE CLEVELAND OH US 44195-0001 (216)445-6440 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
9500 Euclid Avenue Cleveland OH US 44195-0001 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
DMR SHORT TERM SUPPORT, Engineering of Biomed Systems |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.041 |
ABSTRACT
PI: Ramamurthi, Anand/ Rao, Raj R
Proposal Number: 1508642 / 1509377
Restoring structurally damaged soft, elastic tissues to a healthy state is difficult since adult cells are poorly capable of building new elastic fibers, which allow tissues to stretch and recoil. In this project, the investigators propose identification and characterization of factors derived from stem cells towards regenerating and repairing elastic fiber assembly and structure. Further, the studies aim to deliver factors in a sustained manner using degradable polymeric particles which are themselves chemically modified to stimulate new elastic fiber formation and prevent its breakdown. The investigators will then test the effectiveness of the particles in treating abdominal aortic aneurysms, a disorder characterized by breakdown of the structure of the major elastic blood vessel (aorta). In the future, this platform technology can be extended to treat other non-vascular elastic tissue types (e.g., lung tissue) in need of structural repair.
This proposal aims to develop innovative, new approaches to enable in situ, biomimetic elastic matrix regenerative repair in soft, elastic tissues structurally compromised by proteolytic injury. The proposed approach seeks to overcome intrinsically-poor auto-regenerative repair of disrupted elastic matrix by stable adult cell types. The investigators have recently shown bone marrow mesenchymal stem cell (BM-MSC)-derived smooth muscle cells (BM-SMCs), but not undifferentiated BM-MSCs, to be significantly more elastogenic than adult vascular SMCs (healthy, diseased), and their secretions to stimulate elastic matrix regenerative repair by SMCs of a diseased, matrix assembly-impaired phenotype. As physical delivery of stem cells faces several challenges, this project proposes to design and test a stem cell-inspired, but cell-free regenerative approach to in situ ECM regenerative repair. The approach is based on sustained, local delivery of BM-SMC secretome components identified to be necessary and sufficient for pro-elastin regenerative stimulus from novel polymer nanocarriers that themselves exhibit pro-elastogenic and anti-proteolytic properties. Through experiments designed to address three specific aims, the investigators will test hypotheses that a) human BM-MSCs (hBM-MSCs) can be efficiently differentiated into SMCs (hBM-SMCs) exhibiting distinct, elastogenicity-determining phenotypic states; b) pro-elastogenic effects of hBM-SMCs on abdominal aortic aneurysm SMCs are mediated by their secreted trophic factors (secretome); c) key components of hBM-SMC secretome individually or in combination are necessary and sufficient for pro-elastogenic and anti-proteolytic effect; and d) integrating sustained delivery of key hBM-SMC secretome factor(s) with nanocarriers will augment quantity & quality of regenerative elastic matrix repair in an ECM-disrupted, 3-D tissue space. The broad research impact of this project is based on its potential that a novel nanotherapeutic approach may enable regenerative elastic matrix repair that recapitulates regenerative effects of SC secretions. Through this project, the investigators will a) develop educational modules for students at several educational levels to better understand stem cell- and tissue engineering, and b) provide unique inter-institutional collaborative training opportunities for students at Cleveland Clinic and Virginia Commonwealth University. By working through well-established summer internship and outreach programs at these institutions, the investigators will develop educational modules that will benefit high school students, undergraduate students and the general public. This proposal is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division, and by the Biomaterials Program in the Division of Materials Research.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Restoring structurally damaged soft, elastic tissues to a healthy state is difficult since adult cells are poorly capable of building new elastic fibers, which allow tissues to stretch and recoil like a rubber band. In this project, the investigators identified and characterized biological factors released by adult stem cell derived smooth muscle cells which provide a stimulus to diseased cells to repair disrupted elastic fibers and assemble new fibers to replace those lost. Further, based on this information, drugs were released biodegradable polymer beads (nanoparticles) to simulate the regenerative effects of the stem cell secretions. These beads were chemically modified to be able to stimulate new elastic fiber formation and prevent its breakdown and further to enable them to bind to disease tissues to provide a localized stimulus to elastic fiber regenerative repair. The investigators tested the effectiveness of the nanoparticles in the context of treating abdominal aortic aneurysms (AAAs), an example disorder characterized by breakdown of the structure of the major elastic blood vessel (aorta). In the future, this platform technology can be extended to treat other non-vascular elastic tissue types (e.g., lung tissue) in need of structural repair.
Intellectual Merit: The intellectual merit of this proposal is based on its transformative potential in developing an innovative technology based on stem cell mechanism-inspired design of polymer nanoparticles to augment on site regeneration and repair of elastic fibers towards restoring tissue elasticity compromised in disease. In this project, we demonstrated that smooth muscle cells (BM-SMCs) derived from adult bone marrow mesenchymal stem cells (BM-MSCs) exhibit high potential for elastic fiber regeneration and also uniquely provide through secreted biologic factors, a stimulus to elastin regeneration by elastogenically impaired diseased vascular cells, from an example vascular disorder, aortic aneurysms. We showed these biologic factors, including TGF-b1 to promote matrix regeneration by inhibiting a regulatory protein within the cells called JNK. Since cell delivery for therapy has several practical challenges including need for high quality control, we sought to mimic their effects by identifying a drug, doxycycline (DOX) which also promotes elastin regeneration by inhibiting JNK. We developed small polymer beads called nanoparticles to enable localized and predictable release of the drug in the injured vessel wall. The beads were chemically modified with agents which provided synergy to the effects of the released drugs in independently promoting elastic matrix regenerative and anti-degradative outcomes. We have demonstrated that the nanoparticles can specifically bind to the matrix injured tissues and be retained for long term effect by decorating their surface with antibodies against cathepsin K, an enzyme overexpressed specifically in the injured tissue. These project outcomes will advance our progress towards overcoming poor elastin biosynthesis, the critical ‘missing link’ in vascular tissues generated via tissue engineering principles.
Broader Impacts: The broader research impact of this project is the transformative potential of our stem cell inspired nanomedicine approach that addresses a fundamental problem of poor elastic matrix reparative properties of tissues. The cell-free approach we have developed increases the transformative potential of this project since it will likely have fewer risks, complications, and practical difficulties than an in vivo tissue engineering approach involving stem cell delivery, In this collaborative project, we provided education and research training for graduate, undergraduate, and high school students which emphasized an interdisciplinary approach combining principles of stem cell biology, tissue engineering, and nanomaterials. Three doctoral students and one masters student from Case Western Reserve University (CWRU) and Cleveland State University were received training on nanomaterials and stem cell technologies with support from this project, besides three high school students and an undergraduate from CWRU. Through these students, the research and broader science were communicated to high school communities and national scientific conferences. A broader outcome of this project was the student led development of a novel Image-Pro based morphometric technique to quantify elastic fiber properties from histological sections, a critical need in the field to gauge quantity and quality of stimulated elastogenesis.
Last Modified: 09/26/2019
Modified by: Anand Ramamurthi
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