The use of DNA as a therapeutic agent holds great promise for the treatment of genetic disorders and acquired diseases. To this end, nonviral (or artificial) gene delivery systems are attractive because they can circumvent some problems and risks associated with viral gene delivery. However, the efficiency of gene delivery in vivo by artificial systems is presently much lower than that achieved by viruses. It is widely appreciated that DNA condensation (or compaction) is an important component of most approaches to gene delivery. For example, packaging DNA into particles with dimensions smaller than 50 nm would greatly facilitate its diffusion through the intercellular matrix of tissues. Multivalent cations (e.g. spermidine) can cause DNA in solution to collapse into tightly packed toroidal and rod-like particles with overall dimensions of 100-200 nm. The ability to produce DNA particles with smaller and more uniform dimensions could be very useful in the development of nonviral approaches to gene delivery. The goal of this research is to develop methods for controlling the size and shape of particles into which DNA is condensed. Dr. Hud proposes the use of localized static bends, loops and ovals to nucleate condensation along otherwise linear DNA molecules upon their condensation by multivalent cations. It is expected that static loops will promote the formation of toroidal DNA particles with dimensions governed by the diameter of the loop. Alternatively, static oval structures may favor DNA compaction into rod-like particles where rod length is influenced by the length of the oval. This research should demonstrate the extent to which DNA static structures can be used to control DNA condensation. Dr. Hud's results will have direct implications on the feasibility of using static DNA structures in the development of nonviral gene delivery systems.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Lewis, Catherine D
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Georgia Institute of Technology
Schools of Arts and Sciences
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Sarkar, Tumpa; Petrov, Anton S; Vitko, Jason R et al. (2009) Integration host factor (IHF) dictates the structure of polyamine-DNA condensates: implications for the role of IHF in the compaction of bacterial chromatin. Biochemistry 48:667-75
Sarkar, Tumpa; Vitoc, Iulia; Mukerji, Ishita et al. (2007) Bacterial protein HU dictates the morphology of DNA condensates produced by crowding agents and polyamines. Nucleic Acids Res 35:951-61
Vilfan, Igor D; Conwell, Christine C; Sarkar, Tumpa et al. (2006) Time study of DNA condensate morphology: implications regarding the nucleation, growth, and equilibrium populations of toroids and rods. Biochemistry 45:8174-83
Hud, Nicholas V; Vilfan, Igor D (2005) Toroidal DNA condensates: unraveling the fine structure and the role of nucleation in determining size. Annu Rev Biophys Biomol Struct 34:295-318
Sarkar, Tumpa; Conwell, Christine C; Harvey, Lilia C et al. (2005) Condensation of oligonucleotides assembled into nicked and gapped duplexes: potential structures for oligonucleotide delivery. Nucleic Acids Res 33:143-51
Vilfan, Igor D; Conwell, Christine C; Hud, Nicholas V (2004) Formation of native-like mammalian sperm cell chromatin with folded bull protamine. J Biol Chem 279:20088-95
Persil, Ozgul; Santai, Catherine T; Jain, Swapan S et al. (2004) Assembly of an antiparallel homo-adenine DNA duplex by small-molecule binding. J Am Chem Soc 126:8644-5
Conwell, Christine C; Hud, Nicholas V (2004) Evidence that both kinetic and thermodynamic factors govern DNA toroid dimensions: effects of magnesium(II) on DNA condensation by hexammine cobalt(III). Biochemistry 43:5380-7
Jain, Swapan S; Polak, Matjaz; Hud, Nicholas V (2003) Controlling nucleic acid secondary structure by intercalation: effects of DNA strand length on coralyne-driven duplex disproportionation. Nucleic Acids Res 31:4608-15
Conwell, Christine C; Vilfan, Igor D; Hud, Nicholas V (2003) Controlling the size of nanoscale toroidal DNA condensates with static curvature and ionic strength. Proc Natl Acad Sci U S A 100:9296-301

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