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.