The blood brain barrier is a layer of endothelial cells that line the blood vessels in the central nervous system and is supported by other CNS cells such as astrocytes for proper function. The function of the blood brain barrier is to maintain the homeostasis of the CNS and protect the brain from potentially harmful substances circulating in the blood. Owing to its protective function, the blood brain barrier hinders the entry of therapeutic compounds into the central nervous system thereby prohibiting treatment of many neurological diseases. There is a tremendous need to be able to safely and effectively modulate the permeability of the blood brain barrier to allow entry of therapeutic drugs into the brain, as this would have a major impact on treatment for a broad variety of neurological diseases. These include Alzheimer's, Parkinson's, epilepsy, neurological manifestations of HIV-AIDS, neurological sequelae of Lupus, Huntington's disease, brain cancer and many more. Promising therapies are available to treat a wide range of these disorders, however the efficacy of such therapies are not being realized due to the tremendous hurdle posed by the blood brain barrier. We have recently made the novel discovery that extracellular adenosine, a purine nucleoside produced by the body, is a critical modulator of brain endothelial cell permeability. We also have preliminary evidence suggesting that extracellular adenosine may regulate the expression and function of multi drug resistant gene, P-glycoprotein. In this study, we seek to elucidate the molecular and cellular mechanism of adenosine signaling at the level of the blood brain barrier with focus on opening blood brain barrier with the FDA-approved A2A adenosine receptor agonist, Lexiscan. Our central hypothesis is that adenosine receptor signaling in brain endothelial cells regulates endothelial barrier function. We will test this in three specific aims.1.
Specific Aim 1 : Define the extent to which adenosine receptor signaling modulates blood brain barrier permeability in WT and Alzheimer's transgenic mice. 2.
Specific Aim 2 : Elucidate the molecular mechanisms by which AR signaling modulates brain endothelial cell permeability. 3.
Specific Aim 3 : Determine whether activation of adenosine receptors allows entry of anti-beta amyloid antibodies into the CNS to bind to and alter neuritic plaques in an Alzheimer's disease transgenic mouse model. The outcome of these studies will provide new information on adenosine's role in blood brain barrier regulation and shed light on the potential to use this as a drug delivery system to treat a variety of neurological diseases ranging from Alzheimer's to brain tumors.
The blood brain barrier serves to protect the brain from potentially harmful components in the blood, however this protective function makes it very difficult to get therapeutic compounds into the brain to treat neurological diseases such Alzheimer's and to eradicate infectious diseases such as HIV. We have strong preliminary data that demonstrate that extracellular adenosine; a molecule naturally produced by the body can increase the permeability of the blood brain barrier to promote the entry of substances such as therapeutic drugs into the brain. The studies set out in this proposal will help us to understand the mechanism of adenosine's control of the blood brain barrier and to determine if FDA approved adenosinergic drugs can be used as a method of delivering therapeutic drugs to the brain.
