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 sub-lytic 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. Clusterin is a heterodimeric protein that inhibits the TCC in the fluid phase.
Specific Aim 1 is to identify clusterin sequences responsible for its inhibition of the TCC. Experiments are initially designed to identify functional sequences, specifically those at the carboxyl-terminus of clusterin's alpha subunit, using short and chimeric peptides. Subsequent to these studies, point mutations will be introduced into these domains via site-directed mutagenesis to identify functional amino acid residues. The mutant proteins will be expressed, purified, and assayed for their ability to inhibit the TCC.
Specific aim 2 is to identify the domains within the beta subunit that are responsible for its inhibitory activity. Experiments are designed to generate deletion mutants in this region of the protein. The proteins will then be expressed, purified, and analyzed for TCC-inhibitory activity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
5S06GM008008-30
Application #
6450662
Study Section
Project Start
2001-04-01
Project End
2002-03-31
Budget Start
Budget End
Support Year
30
Fiscal Year
2001
Total Cost
$38,454
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