The goal of this proposal is to identify molecular interactions relevant to drug targeting and chemical signaling in cell membranes. More than half the drugs on the market target membrane proteins, a class of molecules where obtaining molecular detail in intact membranes challenges existing methods. We will use the plasmonic properties of nanoparticles to enable chemical-specific spectroscopic studies of ligand-receptor binding in intact cellular membranes. These investigations will demonstrate a new approach to probe the receptor's chemical residues that bind peptide antagonists and provide insight into molecular interactions that regulate the membrane proteins involved in signaling and drug targeting. Our approach combines tip enhanced Raman scattering (TERS), surface plasmon resonance (SPR) spectroscopy, and single particle tracking to characterize chemical interactions that regulate binding to membrane receptors. TERS will determine the chemical residues present in cell membranes that are associated with ligand binding. Initial results obtained in our lab indicate that ligand-functionalized nanoparticles selectively enhance the spectroscopic signals of the receptor involved in ligand binding. The ligand affinity can be determined from proteins immobilized on surfaces using SPR measurements. Complementary measurements can be performed in cells using single particle tracking. By taking advantage of technology that enables tracking of nanoparticles in real-time, we will characterize both ligand binding and membrane organization of individual ligand-functionalized nanoparticles bound to receptors on living cells.
The specific aims of this proposal are: 1) Correlate in situ studies ligand affinity with the molecular identity of the receptor associated with peptide binding to the integrin receptors by combing TERS and SPR. 2) Explore protein receptor-binding interactions in vitro between integrin receptors and peptide ligands using targeted TERS. 3) Correlate in vitro binding affinity with chemical interaction by combining single nanoparticle tracking studies with TERS studies. The technology and platform we propose will address the challenge of obtaining chemical information from ligands binding to receptor proteins in intact cell membranes. These studies will provide new insights into the molecular interactions that regulate signaling pathways and how anomalies in these interactions are associated with disease and treatment.

Public Health Relevance

Membrane receptors are common targets for pharmaceuticals, and increased understanding of the molecular interactions that regulate receptor-ligand interactions in biomembranes will facilitate treatment of disease. This research will develop instrumentation for investigating the binding of molecules to receptors in cellular membranes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
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Smith, Ward
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University of Notre Dame
Schools of Arts and Sciences
Notre Dame
United States
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Xiao, Lifu; Sloan-Dennison, Sian; Schultz, Zachary D (2018) Probing Membrane Receptors with Enhanced Raman Imaging. Proc SPIE Int Soc Opt Eng 10726:
Xiao, Lifu; Schultz, Zachary D (2018) Spectroscopic Imaging at the Nanoscale: Technologies and Recent Applications. Anal Chem 90:440-458
Zeng, Zhi-Cong; Wang, Hao; Johns, Paul et al. (2017) Photothermal Microscopy of Coupled Nanostructures and the Impact of Nanoscale Heating in Surface Enhanced Raman Spectroscopy. J Phys Chem C Nanomater Interfaces 121:11623-11631
Bailey, Karen A; Klymenko, Yuliya; Feist, Peter E et al. (2017) Chemical Analysis of Morphological Changes in Lysophosphatidic Acid-Treated Ovarian Cancer Cells. Sci Rep 7:15295
Kim, Ju-Young; Zeng, Zhi-Cong; Xiao, Lifu et al. (2017) Elucidating Protein/Ligand Recognition with Combined Surface Plasmon Resonance and Surface Enhanced Raman Spectroscopy. Anal Chem 89:13074-13081
Wang, Hao; Yao, Kun; Parkhill, John A et al. (2017) Detection of electron tunneling across plasmonic nanoparticle-film junctions using nitrile vibrations. Phys Chem Chem Phys 19:5786-5796
Xiao, Lifu; Bailey, Karen A; Wang, Hao et al. (2017) Probing Membrane Receptor-Ligand Specificity with Surface- and Tip- Enhanced Raman Scattering. Anal Chem 89:9091-9099
Gu, Xin; Wang, Hao; Schultz, Zachary D et al. (2016) Sensing Glucose in Urine and Serum and Hydrogen Peroxide in Living Cells by Use of a Novel Boronate Nanoprobe Based on Surface-Enhanced Raman Spectroscopy. Anal Chem 88:7191-7
Xiao, Lifu; Schultz, Zachary D (2016) Targeted-TERS detection of integrin receptors on human cancer cells. Cancer Cell Microenviron 3:
Xiao, Lifu; Wang, Hao; Schultz, Zachary D (2016) Selective Detection of RGD-Integrin Binding in Cancer Cells Using Tip Enhanced Raman Scattering Microscopy. Anal Chem 88:6547-53

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