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TRANSCRIPT
To Breathe or Not To Breathe
The Effects of the Hypoxia Inducible Factor-1 on Cell Proliferation of the Spinal Cord
Elizabeth FeldmanPine Crest School
Background
• Hypoxia: Lack of oxygen delivery to tissues with the body
• Chelonia mydas (Green Sea Turtle)
• Born 1 meter beneath the sand; a hypoxic condition
• Live a life of diving • In and out of water, therefore
constantly affected by changes in oxygen levels
• Model Organism to study the effects of Hypoxia
• Hypoxia Inducible Factor-1 • Present in all vertebrates• Active in Chelonia mydas• Not Active in Homo sapiens
Cellular Respiration• Glycolysis does
not require oxygen
• Citric Acid Cycle does require oxygen
• Oxidative Phosphorylation does require oxygen
Affected byHypoxia
No Oxygen Decrease in ATP
production
2 Types of Neurons
• Sodium Potassium Gradient (Na+/K+)• Decreasing ATP levels cause:• Potassium to leave the interior of the cell • Sodium to enter the interior of the cell• Depolarization of the membrane
• Sodium Calcium Gradient (Na+/Ca2+)• Depolarization of the membrane causes:• Calcium is released from interior of the
mitochondria and endoplasmic reticulum • Activation of proteases (ATPase), which
damages the cytoskeleton• Prevents typical synaptic transmission
• Excitatory Amino acid: Glutamate • Glutamate ejected from the interior of the
neuron causes: • Glutamate leads to the activation of
glutamate receptors, initiating the glutamate cascade • Glutamate Cascade: Process of calcium
influx• N-methyl-D-aspartate (NMDA) receptor
activation• Extracellular concentrations now
considered neurotoxic (damaging the function of the nerve tissue)
Hypoxia Intolerant Neuron
© Nunn's Applied Respiratory Physiology
Intolerant Neuron
Tolerant Neuron
2 Types of Neurons
• No Depolarization of the Na+ K+ ion gradient
• Action Potential Threshold caused by a 42% density decrease of the ion channel
• Reduce all aspect of activity in the cell
• Decreases the demand for energy
• Reduces ion permeability (Ion permeability accounts for 50% of ATP demand)
• Contain an Oxygen-Sensing Pathway
• Oxygen-sensitive transcription factor: Hypoxia-Inducible Factor-1 (HIF-1)
Hypoxia Tolerant Neuron
© Nunn's Applied Respiratory Physiology
Intolerant Neuron
Tolerant Neuron
HIF-1 A TRANSCRIPTON FACTOR
• pVHL (growth factor) binds to HIF-1 in the presence of oxygen, causing degradation of the protein
• pVHL does not bind to HIF-1 in the absence of oxygen• Results in the upregulation of genes
required for cell survival • EPO Erythropoiesis (Production of red
blood cells)
• VEGF Angiogenesis (Production of red blood vessels)
• c-Met Mitogenisis (Initiation of Mitosis)
• CXCR4 Vascularization (Begins the remodeling process)
© 2014 Nature Publishing Group, a division of Macmillan Publishers Limited
pVHL
HIF
The Sea Turtles
• 2 Mechanism of survival from hypoxic conditions• Lower heart rate Perseveres
the amount of oxygen • Proliferate cells Replaces the
damaged cells• Cells proliferate specifically
along the spinal cord
• Chelonia mydas have the HIF-1 transcription factor• HIF-1α units promote
proliferation
Application
© 2013 Pearson Education Inc.
• Estimated people living with a spinal cord injury (SCI) ≈ 273,000 people
• Top 3 Causes of SCI :• Automotive
Accidents• Violence• Falling
• SCI causes the loss of…• Movement• Sensation• Bowel/bladder
control• Exaggerated
reflexes• Pain
If HIF-1 can be activated in mammals, then there is a
possibility to begin the effect of cell proliferation and the recovery
process from spinal cord injuries.
Future Research
• How can a hypoxia tolerant neuron reduce the requirements for ATP for cell survival?
• What mechanism prevents pVHL from binding to HIF-1 in absence of Oxygen?
• What therapies can arise from the knowledge known about cell proliferation on the spinal cord resulting from hypoxia?
• "Adaptive responses of vertebrate neurons to hypoxia." The Journal of Experimental Biology 205 (2002): 3579-3586. The Journal of Experimental Biology. Web. 19 Jan. 2014.
• Ke, Q., and M. Costa. "Hypoxia-Inducible Factor-1 (HIF-1)." Molecular Pharmacology 70.5 (2006): 1469-1480. Print.
• Lumb, Andrew B., and J. F. Nunn. Nunn's applied respiratory physiology. 5th ed. Oxford: Butterworth-Heinemann, 2000. Print.
• Price, E, F Paladino, K Strohl, P Santidriant, K Klann, and J Spotila. "Respiration In Neonate Sea Turtles." Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology 146.3 (2007): 422-428. Print.
• "Repair of spinal cord injury by hypoxia-inducible factor-1a-expressing neural stem cells ." Journal of Medical Hypotheses and Ideas 8.1 (2013): 27-29. Science Direct. Web. 15 Dec. 2013.
• Schioppa, T., G. Melillo, A. Saccani, B. Uranchimeg, A. Sica, A. Mantovani, L. Vago, M. Nebuloni, S. Saccani, S. Bernasconi, A. Rapisarda, A. Doni, and S. K. Biswas. "Regulation of the Chemokine Receptor CXCR4 by Hypoxia." Journal of Experimental Medicine 198.9 (2003): 1391-1402. Print.