Objective/Rationale:
Dopamine replacement therapy activates neurons in a particular region of the brain, the striatum, leading to an improvement in disease symptoms. This action occurs through a dopamine receptor - best thought of as an ‘ignition’ - dopamine is a 'key' that turns on the ignition. There is another ‘ignition’ (a receptor), in the same region of brain; it is called GPR88. No one has identified a key to turn it on. Our efforts are focused on finding a key for GPR88. This will open the possibility of turning on GPR88 and determining whether it improves the symptoms of Parkinson’s disease.
Project Description:
Using molecular biology techniques, we can change cells in lab dishes so they produce the GPR88 receptor (the ignition) on their surface. We engineer the cells so that if the GPR88 ignition is turned on with a ‘key’- the cell turns green. In each cell we introduce a random key (produced by a small piece of DNA). We test thousands of different keys in thousands of different cells. If the right DNA enters the cell, it makes a key that turns on GPR88 which in turn results in the cell turning green. We then isolate the green cell, and read the DNA sequence- this provides instructions on how to make the GPR88 key. The Kopin laboratory has recently figured out a new way to generate and test large collections of these keys (which we call “membrane-tethered ligands”). We are hopeful that our efforts will lead to establishing a promising new target for Parkinon’s Disease drugs.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We are working on finding a way to activate a receptor, GPR88, which is enriched in the brain center that controls movement. Our hypothesis is that targeting GPR88 with drugs will open new ways to treat PD, and possibly alleviate the negative effects seen with long term use of classical therapeutics.
Anticipated Outcome:
We plan to further improve the system we use to screen keys so that if needed, we can assess hundreds of thousands of candidate keys. We anticipate finding a GPR88 key, thus setting the stage for defining the role of this receptor in Parkinson’s disease.