Abstract: The extracellular matrix (ECM) is a complex network of collagens, laminins, fibronectins and proteoglycans that provides a surface upon which cells can adhere, differentiate and proliferate. Defects in the ECM are the underlying cause of a wide spectrum of diseases. The ECM mediates endothelial cell polarity and under normal conditions can suppress pre-oncogenic transitions to a neoplastic state. We are constructing artificial, de novo collagen-based matrices using a hierarchic computational approach. These matrices will be physically characterized in the laboratory and used to probe the role of chemical and spatial organization in the ECM on the tumor forming potential of adhered cells. We are using a two-stage, computational strategy to construct an artificial ECM. A key technology is protCAD (protein Computer Automated Design), a software platform developed in our laboratory specifically for computational protein design. In the first stage, the sequences of short collagen-like modules are designed to independently assemble into trimers of programmed stability and specificity. These modules are then covalently connected using flexible peptide linkers to facilitate the selfassembly of controlled higher-order structures such as networks and fibrils. Encouraging experimental characterization of the first generation collagen designs suggests that our computational strategy is likely to succeed. Synthetic ECMs will be useful in biomedical research and translational applications. Mammalian cells will be grown on anisotropic, self-assembling nanostructured matrices to assay effects on cell polarity, cytoskeletal orientation and mophology. We will explore the ability of artificial matrices to suppress cell proliferation in the presence of various oncogenic signals. This will provide a powerful system for studying molecular aspects of the matrix biology of cancer. Successfully designed matrices will be applied to engineering safer artificial tissues. Public Health Relevance: The extracellular matrix is a complex network of proteins that provides a platform for cells to adhere on and assemble into complex tissues. Defects in the extracellular matrix are linked to a number of bowel, bone and skin diseases, autoimmune disorders such as Lupus and a broad range of cancers. Artificial, nano-scale matrices will help us study the role of the matrix in disease, and provide safe biomaterials for tissue engineering.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZGM1-NDIA-O (02))
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Basavappa, Ravi
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Loell, Kaiser; Nanda, Vikas (2018) Marginal protein stability drives subcellular proteome isoelectric point. Proc Natl Acad Sci U S A 115:11778-11783
Xu, Fei; Zheng, Hongning; Clauvelin, Nicolas et al. (2017) Parallels between DNA and collagen - comparing elastic models of the double and triple helix. Sci Rep 7:12802
McGuinness, Kenneth; Nanda, Vikas (2017) Collagen mimetic peptide discs promote assembly of a broad range of natural protein fibers through hydrophobic interactions. Org Biomol Chem 15:5893-5898
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Parmar, Avanish S; James, Jose K; Grisham, Daniel R et al. (2016) Dissecting Electrostatic Contributions to Folding and Self-Assembly Using Designed Multicomponent Peptide Systems. J Am Chem Soc 138:4362-7
Nanda, Vikas; Senn, Stefan; Pike, Douglas H et al. (2016) Structural principles for computational and de novo design of 4Fe-4S metalloproteins. Biochim Biophys Acta 1857:531-538
Pike, Douglas H; Nanda, Vikas (2015) Empirical estimation of local dielectric constants: Toward atomistic design of collagen mimetic peptides. Biopolymers 104:360-70
Parmar, Avanish S; Xu, Fei; Pike, Douglas H et al. (2015) Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides. Biochemistry 54:4987-97
McGuinness, Kenneth; Khan, I John; Nanda, Vikas (2014) Morphological diversity and polymorphism of self-assembling collagen peptides controlled by length of hydrophobic domains. ACS Nano 8:12514-23

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