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Principal Investigator: Ning Fang
Organization: GEORGIA STATE UNIVERSITY
Fiscal Year: 2019
Award: $301,325
Funding agency: National Institute of General Medical Sciences
DESCRIPTION (provided by applicant): Viruses, drug delivery vectors, and other external particles exhibit a variety of complex behaviors on and in the cell membrane that are reflective of their physical and chemical properties, including size, shape, charge and the availability of membrane receptors, before they trigger internalization pathways to enter the cell. Understanding the dynamics of these cellular membrane processes is essential for many important human health related problems, such as the rational design of nanoparticle-based drug delivery systems and the prevention and control of infectious pathogens. The past efforts provided excellent visualization of cellular membrane processes, but primarily for translational dynamics. This proposal focuses on utilizing the recently-developed single particle orientation and rotational tracking (SPORT) technique to elucidate the characteristic live-cell rotational dynamics. SPORT affords high spatial, angular, and temporal resolutions simultaneously, for visualizing the rotational dynamics of anisotropic plasmonic gold nanorods in live cells in differential interference contrast (DIC) microscopy. By using SPORT, the proposed research will acquire new fundamental knowledge about the detailed rotational dynamics of cellular membrane processes, such as adhesion, transport, and endocytosis of functionalized nanoparticles, as may be relevant to drug delivery and viral entry. The rotational patterns on cell
membranes for functionalized gold nanorods will be identified and correlated with their lateral movements and the presence of relevant functional biomolecules tagged with fluorescent proteins. The characteristic rotational motions of cargos during different internalization pathways
will also be visualized directly, leading to new opportunities for understanding the timing, signaling and chemical and mechanical functions of protein modules involved in different pathways. Computer simulations will be developed to understand the effects of nanoparticle shapes, sizes and surface modifiers. The simulations will aid the project by providing suggestions for further informative experiments. Finally, SPORT will be utilized to study the uptake mechanism of aptamer-loaded gold nanostars in cancer cells. The proposed research may initiate a shift in the current research paradigm on membrane structure and function by demonstrating the importance of rotational dynamics at the single molecule and nanoparticle level. A thorough understanding of the fundamental motions in evidence will inform about the details of the molecular mechanisms involved in the diffusion of membrane proteins and parallel internalization pathways that will be critical for the better design of antiviral drugs, as well asthe development of targeted delivery vehicles and anti-cancer medicines.
Terms: <Adhesions><Antiviral Agents><Antiviral Drugs><Antivirals><Behavior><Binding><Biological Function><Biological Process><Biophysics><Cell Body><Cell Communication and Signaling><Cell Function><Cell Membrane Lipid Rafts><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cells><Cellular Function><Cellular Membrane><Cellular Physiology><Cellular Process><Characteristics><Charge><Chemicals><Complex><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Coupling><Cytoplasm><Cytoplasmic Membrane><DNA><Deoxyribonucleic Acid><Development><Diagnostic><Differential Interference Contrast Microscopy><Diffusion><Disease><Disorder><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drugs><Endocytosis><Exhibits><General Viruses><Gold><Health><Human><Imagery><Imaging Device><Imaging Instrument><Imaging Tool><Imaging technology><Intracellular Communication and Signaling><Knowledge><Lateral><Lead><Ligands><Malignant Cell><Mathematical Model Simulation><Mathematical Models and Simulations><Mechanics><Medical><Medication><Medicine><Membrane><Membrane Microdomains><Membrane Protein Gene><Membrane Proteins><Membrane Structure and Function><Membrane-Associated Proteins><Microscope><Modern Man><Molecular><Molecular Interaction><Motion><Movement><Nomarski Interference Contrast Microscopy><Optics><Pathway interactions><Pattern><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphoproteins><Plasma Membrane><Prevention><Process><Proteins><Receptor Protein><Research><Rotation><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Subcellular Process><Suggestion><Surface><Surface Proteins><Techniques><Testing><Therapeutic><Viral><Virus><Visualization><anti-cancer><anti-viral agents><anti-viral drugs><anti-virals><anticancer><aptamer><base><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><body movement><cancer cell><chemical property><computational modeling><computational models><computational simulation><computer based models><computerized modeling><computerized simulation><design><designing><developmental><drug/agent><effective therapy><effective treatment><experiment><experimental research><experimental study><extracellular><heavy metal Pb><heavy metal lead><improved><in silico><innovate><innovation><innovative><insight><lipid raft><live cell image><live cell imaging><live cellular image><live cellular imaging><mechanical><membrane structure><nano><nano particle><nano particle drug><nano probe><nano rod><nano-sized particle><nanoparticle><nanoparticle drug><nanoprobe><nanorod><nanosized particle><new approaches><novel><novel approaches><novel strategies><novel strategy><nucleolin><optic imaging><optical><optical imaging><overexpress><overexpression><particle><pathogen><pathway><physical property><plasmalemma><plasmonics><protein function><public health relevance><receptor><simulation><single molecule><site targeted delivery><targeted delivery><temporal measurement><temporal resolution><time measurement><tool><uptake><vector><virtual simulation>