Abstract

application): This pilot project deals with elucidation of mechanisms involved in the DNA/lipid complex-induced toxicity in CF patient during cationic liposome-mediated gene therapy. The symptoms observed include fever, myalgia and arthralgia, occurring at six hours with full recovery between 24-48 hours after the administration of DNA/lipid 67 complexes. The applicant believes that the toxic effects of DNA/lipid complexes are caused by unmethylated CpG motif in plasmid DNA. It is hypothesized that CpG motif activates T lymphocytes and macrophages to release inflammatory cytokines (TNF-a and IL-1), Th1-inducing cytokines (IL-12 and IL-18), Th-1 cytokine (IFN-r), leading to fever, myalgia, arthralgia and activation of NK and B cells. The applicant has proposed two Specific Aims to test his hypothesis.
Aim 1 is to explore the effect of methylated and unmethylated CpG motifs of plasmid DNA in the presence or absence of lipid 67 on the production of specific cytokines in human peripheral blood cells (PBMCs) in vitro, and to test the effect of anti-inflammatory cytokines IL-10 and IL-4 on the production of the specific cytokines.
Aim 2 deals with similar experiments in vivo using IL-12 or IFN-r knock out mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
5P30DK054781-04
Application #
6564368
Study Section
Project Start
2002-01-01
Project End
2002-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
2002
Total Cost
$165,355
Indirect Cost

  Institution

Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

Blount, Angela; Zhang, Shaoyan; Chestnut, Michael et al. (2011) Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium. Laryngoscope 121:1929-34
Havasi, Viktoria; Rowe, Steven M; Kolettis, Peter N et al. (2010) Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. Fertil Steril 94:2122-7
Su, Xuefeng; Li, Qingnan; Shrestha, Kedar et al. (2006) Interregulation of proton-gated Na(+) channel 3 and cystic fibrosis transmembrane conductance regulator. J Biol Chem 281:36960-8
Sorscher, E J; Harris, J; Alexander, M et al. (2006) Activators of viral gene expression in polarized epithelial monolayers identified by rapid-throughput drug screening. Gene Ther 13:781-8
Joung, Insil; Harber, Greg; Gerecke, Kimberly M et al. (2005) Improved gene delivery into neuroglial cells using a fiber-modified adenovirus vector. Biochem Biophys Res Commun 328:1182-7
Bebok, Zsuzsa; Collawn, James F; Wakefield, John et al. (2005) Failure of cAMP agonists to activate rescued deltaF508 CFTR in CFBE41o- airway epithelial monolayers. J Physiol 569:601-15
Joung, Insil; Kim, Hak Jae; Kwon, Yunhee Kim (2005) p62 modulates Akt activity via association with PKCzeta in neuronal survival and differentiation. Biochem Biophys Res Commun 334:654-60
Hentchel-Franks, Karen; Lozano, David; Eubanks-Tarn, Valerie et al. (2004) Activation of airway cl- secretion in human subjects by adenosine. Am J Respir Cell Mol Biol 31:140-6
Pittler, Steven J; Zhang, Youwen; Chen, Shiming et al. (2004) Functional analysis of the rod photoreceptor cGMP phosphodiesterase alpha-subunit gene promoter: Nrl and Crx are required for full transcriptional activity. J Biol Chem 279:19800-7
White, J Brandon; Thompson, W Joseph; Pittler, Steven J (2004) Characterization of 3',5' cyclic nucleotide phosphodiesterase activity in Y79 retinoblastoma cells: absence of functional PDE6. Mol Vis 10:738-49

Showing the most recent 10 out of 57 publications