Abstract

Maintaining oxygen homeostasis is critical for human life. Hypoxic stress has been associated with ischemic stroke, tumor growth and fatigue in exercise. Yet molecular mechanisms underlying cellular response to low oxygen - in healthy humans, let alone in disease - have largely eluded researchers. The 1993 discovery of hypoxia-inducible factor 1 (HIF1), a transcription factor that activates over 70 genes, shed some light onto how cells sense and react to oxygen levels. In this proposal, computational methods will be used to develop a theoretical model of HIF1 pathways. The model, comprised of biochemical kinetic equations and transfer functions that represent HIF1 alpha degradation and HIF1 synthesis, will test hypotheses about the fundamental molecular mechanisms of vascular adaptation in hypoxia.
In Specific Aim 1, the model will be used to predict the sensitivity of the HIF1 pathway to p53 and prolyl hydroxylase concentrations in varying degrees of hypoxia.
In Specific Aim 2, differential effects of intermittent and chronic hypoxia on HIF1 alpha degradation will be characterized. Computational results will be validated by experimental data.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL085016-03
Application #
7413597
Study Section
Special Emphasis Panel (ZRG1-BST-A (20))
Program Officer
Rothgeb, Ann E
Project Start
2006-05-04
Project End
2009-06-28
Budget Start
2008-05-04
Budget End
2009-06-28
Support Year
3
Fiscal Year
2008
Total Cost
$50,428
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Qutub, Amina A; Mac Gabhann, Feilim; Karagiannis, Emmanouil D et al. (2009) Multiscale models of angiogenesis. IEEE Eng Med Biol Mag 28:14-31
Qutub, Amina A; Liu, Gang; Vempati, Prakash et al. (2009) Integration of angiogenesis modules at multiple scales: from molecular to tissue. Pac Symp Biocomput :316-27
Qutub, Amina A; Popel, Aleksander S (2009) Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting. BMC Syst Biol 3:13
Qutub, Amina A; Popel, Aleksander S (2008) Reactive oxygen species regulate hypoxia-inducible factor 1alpha differentially in cancer and ischemia. Mol Cell Biol 28:5106-19
Qutub, Amina A; Popel, Aleksander S (2007) Three autocrine feedback loops determine HIF1 alpha expression in chronic hypoxia. Biochim Biophys Acta 1773:1511-25
Qutub, Amina A; Popel, Aleksander S (2006) A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha. J Cell Sci 119:3467-80