Grant: Project Grant

In the absence of sufficient oxygen (i.e. during hypoxia), cells die. When oxygen levels are low but not lethal, cells can cope by changing how they metabolize nutrients: they use alternate mechanisms that do not depend so heavily on oxygen, and at the same time increase the capacity for oxygen to be delivered (increasing the number of red blood cells and blood vessels, for example). Interestingly, these mechanisms are also partially engaged when nerves are injured, as they are in 2-3% of all injuries to any part of the body. Nerve injury leads to loss of function (sensation and movement, for example), as well as to neuropathic pain, most frequently described as unpleasant burning, electric shock-like, or crushing sensations. Often these consequences of nerve injury fail to resolve, prompting us to ask whether artificially engaging the hypoxia response can improve peripheral nerve regeneration and reduce neuropathic pain. Our cells "know" how much oxygen is present by virtue of oxygen-sensing proteins called PHDs. There are three of these: PHD1, 2 and 3. When these proteins are blocked with a drug (DMOG), or genetically silenced, cells are "tricked" into behaving as they would under hypoxia. We will use DMOG and PHD-deficient mice to ask whether and how mimicking hypoxia can improve recovery, including preventing neuropathic pain, following nerve injury.