The overall aim of this competing renewal is to study the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits. The currently proposed project has evolved from our NIH-supported studies, which demonstrated that the formation of collagen fibrils, a main component of fibrotic tissues, can be suppressed by inhibitors that block site-specific collagen/collagen interactions that drive collagen self-assembly. Thus, the main hypothesis presented here is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue. To test this hypothesis, we propose three Specific Aims: (1) to select inhibitors with specific affinities for binding the sites that control collagen I self- assembly. (2) To stabilize and test the selected inhibitors in vitro for their potential to inhibit collagen fibril formation. (3) To determine the effectiveness of inhibitors of localized fibrosis in a keloid-like model. The experimental model we will employ to test our hypothesis will include monoclonal antibodies and synthetic peptides that specifically bind to the sites that participate in the collagen/collagen interaction. We plan to determine the clinical utility of the proposed inhibitors by employing in vitro and in vivo analyses. Although our study will investigate the usefulness of the proposed method to inhibit localized fibrosis in skin, we expect that the results of our study will have a broad positive impact on limiting the formation of fibrotic deposits in other tissues. This notion is based on the fact that, irrespective of etiology, the fibrotic process always includes excessive accumulation of collagen fibrils. Thus, the expected broad impact of our proposed study on preventing devastating effects of fibrosis is high.

Public Health Relevance

Fibrosis is a serious medical problem that affects all collagen-rich connective tissues. Because one of the hallmarks of fibrosis is excessive accumulation of collagen fibrils, the objective of the proposed study is to develop novel approaches to limit fibrosis by inhibiting the extracellular process of collagen fibril assembly. Since results of our study will establish the basis for new treatments of pathological changes caused by fibrosis, the relevance of our proposed research for public health is high.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048544-09
Application #
8606407
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (05))
Program Officer
Tseng, Hung H
Project Start
2002-05-13
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$313,875
Indirect Cost
$111,375
Name
Thomas Jefferson University
Department
Dermatology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Fertala, Jolanta; Kostas, James; Hou, Cheryl et al. (2014) Testing the anti-fibrotic potential of the single-chain Fv antibody against the *2 C-terminal telopeptide of collagen I. Connect Tissue Res 55:115-22
Fertala, Jolanta; Steplewski, Andrzej; Kostas, James et al. (2013) Engineering and characterization of the chimeric antibody that targets the C-terminal telopeptide of the *2 chain of human collagen I: a next step in the quest to reduce localized fibrosis. Connect Tissue Res 54:187-96
Lee, Boyeon; Clarke, Douglas; Al Ahmad, Abraham et al. (2011) Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents. J Clin Invest 121:3005-23
Sweeney, Shawn M; Orgel, Joseph P; Fertala, Andrzej et al. (2008) Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem 283:21187-97
Chung, Hye Jin; Steplewski, Andrzej; Chung, Kee Yang et al. (2008) Collagen fibril formation. A new target to limit fibrosis. J Biol Chem 283:25879-86
Hintze, Vera; Steplewski, Andrzej; Ito, Hidetoshi et al. (2008) Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis. Hum Mutat 29:841-51
Cabral, Wayne A; Makareeva, Elena; Letocha, Anne D et al. (2007) Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum Mutat 28:396-405
Steplewski, Andrzej; Hintze, Vera; Fertala, Andrzej (2007) Molecular basis of organization of collagen fibrils. J Struct Biol 157:297-307
Ito, Hidetoshi; Rucker, Eileen; Steplewski, Andrzej et al. (2005) Guilty by association: some collagen II mutants alter the formation of ECM as a result of atypical interaction with fibronectin. J Mol Biol 352:382-95
Steplewski, Andrzej; Brittingham, Raymond; Jimenez, Sergio A et al. (2005) Single amino acid substitutions in the C-terminus of collagen II alter its affinity for collagen IX. Biochem Biophys Res Commun 335:749-55

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