Collagen is the most abundant protein in humans, comprising 1/3 of the total protein and 3/4 of the dry weight of skin. Collagen abnormalities are associated with many human diseases, including arthritis. The overall objective of the proposed research is to reveal the chemical basis for the unique triple-helical structure of collagen, and t devise new therapies based on that knowledge.
Specific Aims : The four Specific Aims of this research proposal apply methods and ideas from physical organic chemistry, peptide chemistry, molecular self-assembly, chemical enzymology, and matrix biology.
Aim 1 is to discern whether enhancing a newly appreciated physicochemical force-the n->?* interaction-can increase triple-helix stability.
Aim 2 is to create collagen mimetic peptides that self-assemble into human-scale triple helices that are useful for biomedical applications.
Aim 3 is to gain insight into the mechanism of catalysis by human prolyl 4-hydroxylase, which is the enzyme that installs the prevalent and important 4-hydroxyproline residues in collagen strands and is a target for the treatment of fibrotic diseases. Finally, Aim 4 is to use extant knowledge of collagen to create peptide conjugates to assess and heal wounds in mice. Significance: The results of the research proposed herein will provide fundamental insights into the structure and conformational stability of the collagen triple helix, and will use those insights to create transformative molecular therapies for wound care, which now accounts for up to $15B annually in US health care costs, and other indications.

Public Health Relevance

This research project is focused on collagen, which is the most abundant protein in humans. Collagen abnormalities are associated with a variety of human diseases, including arthritis. The goal of the project is to obtain insights into the relationship between the amino acid sequence of collagen and its biological function (or dysfunction), as well as to create novel collagen-like proteins of therapeutic use in wound healing and other indications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044276-18
Application #
8632991
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Tseng, Hung H
Project Start
1996-07-15
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
$380,080
Indirect Cost
$122,972
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Tanrikulu, I Caglar; Forticaux, Audrey; Jin, Song et al. (2016) Peptide tessellation yields micrometre-scale collagen triple helices. Nat Chem 8:1008-1014
Vasta, James D; Andersen, Kristen A; Deck, Kathryn M et al. (2016) Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells. ACS Chem Biol 11:193-9
Vasta, James D; Choudhary, Amit; Jensen, Katrina H et al. (2016) Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (E)- or (Z)-Alkene Replaces the Prolyl Peptide Bond. Biochemistry :
Vasta, James D; Raines, Ronald T (2016) Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center. Biochemistry 55:3224-33
Newberry, Robert W; Raines, Ronald T (2016) A prevalent intraresidue hydrogen bond stabilizes proteins. Nat Chem Biol 12:1084-1088
Newberry, R W; Raines, R T (2016) Crystal structure of N-(3-oxo-butano-yl)-l-homoserine lactone. Acta Crystallogr E Crystallogr Commun 72:136-9
Newberry, Robert W; Orke, Samuel J; Raines, Ronald T (2016) n→π* Interactions Are Competitive with Hydrogen Bonds. Org Lett 18:3614-7
Chattopadhyay, Sayani; Guthrie, Kathleen M; Teixeira, Leandro et al. (2016) Anchoring a cytoactive factor in a wound bed promotes healing. J Tissue Eng Regen Med 10:1012-1020
Arnold, Ulrich; Raines, Ronald T (2016) Replacing a single atom accelerates the folding of a protein and increases its thermostability. Org Biomol Chem 14:6780-5
Vasta, James D; Raines, Ronald T (2015) Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates. Bioorg Med Chem 23:3081-90

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