Recent breakthroughs in molecular biotechnology are allowing simultaneous measurements of thousands of gene products in a single experiment. Understanding the complexity of such datasets requires a thorough training in both traditional molecular biology and computational sciences. The primary goal of this mentored development award is to provide the Principal Investigator (PI) the training and environmental support necessary to develop into an independent computational molecular biologist in the field of cardiopulmonary biology. This multidisciplinary award will support the PI's training in the disciplines of physiology, molecular biology, computational biology and statistics, and allow him to combine these tools to investigate the molecular basis of pulmonary hypertension and right ventricular remodeling. The primary scientific goal of this project is to discover several key genetic pathways in the pathogenesis of pulmonary hypertension and right ventricular hypertrophy (RVH) by applying rigorous statistical methods to data generated from global gene expression profiling. Two concurrent but interdependent Specific Aims will be pursued.
Aim 1 will identify, characterize and confirm a set of temporally and functionally related genes that are crucial in the development and regression of pulmonary hypertension and RVH in mice. Different mouse models of pulmonary hypertension and RVH will be compared to search for common genetic pathways during both the progression and regression of these processes. Additionally, the hypothesis that pulmonary vascular and right ventricular remodeling share several common molecular pathways will be tested. This approach will uniquely provide global insights into the complex molecular processes activated during vascular and ventricular remodeling.
Aim 2 will allow the PI to develop and improve computational methods to normalize raw data, determine statistically significant gene expression, and apply clustering strategies to microarray-generated datasets. The results of investigations undertaken in Aim 2 will be applied directly to data generated in Aim 1. Pursuit of a Master's of Science in Computational Biology will further enhance the PI's ability to successfully merge complex mathematical models with datasets resulting from large-scale gene expression profiling. Ultimately, this mentored research career award will allow the PI to develop into an independent computational molecular biologist and pursue an academic research career in the physiologic genomics of the cardiopulmonary system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL074223-01
Application #
6676772
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2003-07-10
Project End
2008-06-30
Budget Start
2003-07-10
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$129,060
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Khalyfa, Abdelnaby; Gharib, Sina A; Kim, Jinkwan et al. (2011) Peripheral blood leukocyte gene expression patterns and metabolic parameters in habitually snoring and non-snoring children with normal polysomnographic findings. Sleep 34:153-60
Smith, Lincoln S; Gharib, Sina A; Frevert, Charles W et al. (2010) Effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice. Am J Respir Cell Mol Biol 43:475-86
Khalyfa, Abdelnaby; Gharib, Sina A; Kim, Jinkwan et al. (2010) Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea. Am J Respir Crit Care Med 181:1114-20
Becker, Lev; Gharib, Sina A; Irwin, Angela D et al. (2010) A macrophage sterol-responsive network linked to atherogenesis. Cell Metab 11:125-35
Gharib, S A; Nguyen, E; Altemeier, W A et al. (2010) Of mice and men: comparative proteomics of bronchoalveolar fluid. Eur Respir J 35:1388-95
Gharib, Sina A; Vaisar, Tomas; Aitken, Moira L et al. (2009) Mapping the lung proteome in cystic fibrosis. J Proteome Res 8:3020-8
Gharib, Sina A; Liles, W Conrad; Klaff, Lindy S et al. (2009) Noninjurious mechanical ventilation activates a proinflammatory transcriptional program in the lung. Physiol Genomics 37:239-48
Fu, Xiaoyun; Gharib, Sina A; Green, Pattie S et al. (2008) Spectral index for assessment of differential protein expression in shotgun proteomics. J Proteome Res 7:845-54
Seng, Kok-Yong; Glenny, Robb W; Madtes, David K et al. (2008) Comparison of statistical data models for identifying differentially expressed genes using a generalized likelihood ratio test. Gene Regul Syst Bio 2:125-139
Lovegrove, Fiona E; Gharib, Sina A; Pena-Castillo, Lourdes et al. (2008) Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria model. PLoS Pathog 4:e1000068

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