This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Albert Cunningham, PI This project will use structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence. This subproject has three specific aims: 1. Model Development: Update existing SAR models for rodent carcinogenicity that will serve as """"""""control"""""""" models and a set of """"""""experimental"""""""" SAR models based on target tissue-specific chemical carcinogenesis. The control models will be based on the traditional SAR approach of contrasting carcinogens to noncarcinogens and the experimental models will be based on a new approach of contrasting chemical carcinogens from one site to those of all other sites. In essence, the control models will handle the question of """"""""What makes a chemical a carcinogen?"""""""" and the experimental models will tackle the problem of """"""""What makes a carcinogen target a specific tissue?"""""""" This aim will use the Core C facility (Molecular Modeling) to carry out this approach. 2. Toxicophore Identification: Based on information developed in Aim 1, we will identify toxicophore-defined sets of compounds (i.e., with similar structure and biological activity) associated with tissue-specific carcinogenesis. Then we will refine toxicophores from these models with ligand-based 3D SAR methods and develop small libraries of suitable compounds for in vitro testing.
This aim will use Core C (Molecular Modeling). 3. Genome/Proteome Target Identification: Using the compounds from the toxicophore libraries developed in Aim 2 as chemical probes, we will assay site-matched cell lines in order to identify the molecular targets with which they interact. Comparative toxicogenomics and proteomics will be used to identify the specific molecular targets associated with tissue-specific carcinogenicity.
This aim will use Cores B (Microarray facility).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018733-09
Application #
8360669
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$237,513
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Zhao, Guoping; Neely, Aaron M; Schwarzer, Christian et al. (2016) N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins. Oncotarget 7:5924-42
Donninger, Howard; Schmidt, M Lee; Mezzanotte, Jessica et al. (2016) Ras signaling through RASSF proteins. Semin Cell Dev Biol 58:86-95
Garbett, Nichola C; Brock, Guy N (2016) Differential scanning calorimetry as a complementary diagnostic tool for the evaluation of biological samples. Biochim Biophys Acta 1860:981-9
Lanceta, Lilibeth; Mattingly, Jacob M; Li, Chi et al. (2015) How Heme Oxygenase-1 Prevents Heme-Induced Cell Death. PLoS One 10:e0134144
Zhao, Guoping; Lu, Huayi; Li, Chi (2015) Proapoptotic activities of protein disulfide isomerase (PDI) and PDIA3 protein, a role of the Bcl-2 protein Bak. J Biol Chem 290:8949-63
Garbett, Nichola C; Mekmaysy, Chongkham S; DeLeeuw, Lynn et al. (2015) Clinical application of plasma thermograms. Utility, practical approaches and considerations. Methods 76:41-50
Donninger, Howard; Calvisi, Diego F; Barnoud, Thibaut et al. (2015) NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2. J Cell Biol 208:777-89
Sellers, Katherine; Fox, Matthew P; Bousamra 2nd, Michael et al. (2015) Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Invest 125:687-98
Donninger, Howard; Clark, Jennifer; Rinaldo, Francesca et al. (2015) The RASSF1A tumor suppressor regulates XPA-mediated DNA repair. Mol Cell Biol 35:277-87
Schwarzer, Christian; Fu, Zhu; Morita, Takeshi et al. (2015) Paraoxonase 2 serves a proapopotic function in mouse and human cells in response to the Pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-homoserine lactone. J Biol Chem 290:7247-58

Showing the most recent 10 out of 144 publications