The cellular response to injury and inflammation is a fundamental component of several major human diseases. In this proposal, the investigators will seek to elucidate the basic mechanisms underlying these responses through a combination of genomic and proteomic approaches linking the responses to the genes and proteins involved. For the purposes of this proposal, injury is defined in the broadest sense and will encompass diverse, clinically relevant, pathogenic stimuli. The proposal encompasses four major steps. First, the investigators will use microarray-based methods to identify major genes involved in the responses of selected cell types to defined inflammatory or injurious stimuli. Second, the investigators will screen these genes for DNA sequence polymorphisms. Additional candidate genes selected by clinical criteria or by a polymorphism prediction algorithm will also be screened. Third, the investigators will perform association studies to assess the clinical significance of these polymorphisms. Fourth, the investigators will develop reagents (antibodies and peptides) with which to perform functional studies of a selected subset of these genes. The program is organized as a linear sequence of steps, in which the output from one project provides an experimental basis for the following project. Since each project is guided by the results of the preceding project, the cumulative output of the integrated Program in Genomic Applications (PGA) is far more valuable than what could be achieved by each project in isolation. The central biological theme of the program is inflammation and tissue remodeling, to be studied explicitly in the clinical context of cardiovascular disease. There is a strong rationale for this particular focus, based on four fundamental considerations. First, inflammation and tissue remodeling are biological processes pertinent to many clinical disorders. Although selected features of these processes may be unique to a given tissue or disease context, other aspects will prove to be universal. Thus, reagents developed for allelotyping and functional assessment of gene products produced from polymorphic genes will find broad application in heart, lung and blood research. Second, by studying inflammation and tissue remodeling in the specific context of cardiovascular diseases, the investigators attack those conditions that represent leading causes of death and disability among Americans today. Third, this particular focus will allow the investigators to amplify the impact of funds provided by the PGA, by linking this proposal to the recently funded Reynolds grant to Southwestern that will provide a unique tissue remodeling are complex biological processes that are ideally suited to a genomic scale approach.
The aims and experimental design of this PGA are therefore highly congruent with the RFA solicitation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL066880-04
Application #
6652508
Study Section
Special Emphasis Panel (ZHL1-CSR-L (S2))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-09-30
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$3,489,736
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Garner, H R (2011) Combating unethical publications with plagiarism detection services. Urol Oncol 29:95-9
McIver, L J; Fondon 3rd, J W; Skinner, M A et al. (2011) Evaluation of microsatellite variation in the 1000 Genomes Project pilot studies is indicative of the quality and utility of the raw data and alignments. Genomics 97:193-9
Galindo, Cristi L; McIver, Lauren J; Tae, Hongseok et al. (2011) Sporadic breast cancer patients' germline DNA exhibit an AT-rich microsatellite signature. Genes Chromosomes Cancer 50:275-83
Crozier, Stephen P; Garner, Harold R (2007) Ensemble-based RNA secondary structure characterization. IEEE Eng Med Biol Mag 26:72-86
Yi, Ming; Horton, Jay D; Cohen, Jonathan C et al. (2006) WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data. BMC Bioinformatics 7:30
Zhao, Xiao-Song; Pan, Wentong; Bekeredjian, Raffi et al. (2006) Endogenous endothelin-1 is required for cardiomyocyte survival in vivo. Circulation 114:830-7
Wren, Jonathan D; Bekeredjian, Raffi; Stewart, Jelena A et al. (2004) Knowledge discovery by automated identification and ranking of implicit relationships. Bioinformatics 20:389-98
Cohen, Jonathan C; Kiss, Robert S; Pertsemlidis, Alexander et al. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305:869-72
Schageman, Jeoffrey J; Horton, Christopher J; Niu, Sijing et al. (2004) ELXR: a resource for rapid exon-directed sequence analysis. Genome Biol 5:R36
Tang, Fuqiang; Flood, Elizabeth M; Pertsemlidis, Alexander et al. (2003) SNPCEQer II: the integrated detection and analysis of SNPs in DNA sequences. Appl Bioinformatics 2:151-4

Showing the most recent 10 out of 23 publications