1. To Breathe or Not To Breathe
The Effects of the Hypoxia Inducible Factor-1 on Cell Proliferation
of the Spinal Cord
Elizabeth Feldman
Pine Crest School

2. 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

3. Cellular Respiration
• Glycolysis does not
require oxygen
• Citric Acid Cycle
does require oxygen
• Oxidative
Affected by
Phosphorylation
Hypoxia
does require oxygen
No Oxygen 
Decrease in ATP
production

4. 2 Types of Neurons
Hypoxia Intolerant Neuron
•
Sodium Potassium Gradient (Na+/K+)
•
Sodium Calcium Gradient (Na+/Ca2+)
•
Excitatory Amino acid: Glutamate
• Decreasing ATP levels cause:
• Potassium to leave the interior of the cell
• Sodium to enter the interior of the cell
• Depolarization of the membrane
• 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
• 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)
© Nunn's Applied Respiratory Physiology

5. 2 Types of Neurons
Hypoxia Tolerant Neuron
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)
© Nunn's Applied Respiratory Physiology

6. HIF-1
A TRANSCRIPTON FACTOR
• pVHL (growth factor) binds to HIF-1
in the presence of oxygen, causing
degradation of the protein
pVHL
• pVHL does not bind to HIF-1 in the
absence of oxygen
HIF
© 2014 Nature Publishing Group, a division of Macmillan Publishers Limited
• 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)

7. 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

8. Application
• 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
© 2013 Pearson Education Inc.

9. 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.

10. 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?

11. •
"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): 14691480. Print.
•
Lumb, Andrew B., and J. F. Nunn. Nunn's applied respiratory physiology. 5th ed. Oxford: ButterworthHeinemann, 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.