Abstract

The long term objective is to develop ways to differentially regulate the terminal complement complex (TCC) in order to inhibit its cytolytic activity without interfering with activities that require sublytic insertion of the complex into membranes, e.g., in signal transduction. This would be helpful in such areas as atherosclerosis and Alzheimer's disease, both of which involve complement-mediated cytolysis.
Specific aim l is to determine the apolipoprotein J (apoJ) - TCC interactions that are important for the association and inhibition of TCC activity in vitro. To address this question, experiments will be performed to l) ascertain whether apoJ and/or either of its two subunits interferes with the assembly of any individual component into the terminal complex, and 2) determine whether apoJ and/or either of its two subunits can directly inhibit C9 polymerization.
Specific aim 2 is to identify apoJ sequences responsible for its interaction with and inhibition of the TCC. Experiments are designed to identify functional domains, specifically those in the alpha subunit, using peptides, and to introduce point mutations into these domains via site-directed mutagenesis to identify functional amino acid residues.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
5S06GM008008-28
Application #
6107008
Study Section
Project Start
1999-04-01
Project End
2000-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
28
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Xavier University of Louisiana
Department
Type
DUNS #
020857876
City
New Orleans
State
LA
Country
United States
Zip Code
70125

  Publications

Shimada, Tsutomu; Takenaka, Shigeo; Kakimoto, Kensaku et al. (2016) Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. Chem Res Toxicol 29:1029-40
Shimada, Tsutomu; Takenaka, Shigeo; Murayama, Norie et al. (2016) Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13. Xenobiotica 46:211-24
Liu, Jiawang; Pham, Peter T; Skripnikova, Elena V et al. (2015) A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2. J Med Chem 58:6481-93
Goyal, Navneet; Liu, Jiawang; Lovings, La'Nese et al. (2014) Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1. Chem Res Toxicol 27:1431-9
Liu, Jiawang; Taylor, Shannon F; Dupart, Patrick S et al. (2013) Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1. J Med Chem 56:4082-92
Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF CARBAZOLE ANALOGS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:92-95
Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF A FAMILY OF PROPARGYL PYRIDINYL ETHERS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:91-94
Shimada, Tsutomu; Kim, Donghak; Murayama, Norie et al. (2013) Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition. Chem Res Toxicol 26:517-28
Liu, Jiawang; Sridhar, Jayalakshmi; Foroozesh, Maryam (2013) Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules 18:14470-95
Liu, Jiawang; Nguyen, Thong T; Dupart, Patrick S et al. (2012) 7-Ethynylcoumarins: selective inhibitors of human cytochrome P450s 1A1 and 1A2. Chem Res Toxicol 25:1047-57

Showing the most recent 10 out of 34 publications