Grant: Project Grant

Drug discovery was historically based in animal models of disease- which while being a slow process, was fairly successful In the modern era, we have move away from experiments in animals, because of technologies that have allowed us to screen many more drug candidates in cell systems that express the target of interest. These gains in speed have not led reliably to more successful drug discovery programs- to a large extent because they rely on what are called generic or "heterologous" cultured cells that most probably do not accurately reflect the tissue or cell type affected in the disease we are trying to treat such as Parkinson's Disease or chronic neuropathic pain. However, in recent years a whole new set of technological improvements has allowed us to use primary cells from animal (or even stem cells from patients) to screen for drugs in this more relevant physiological and pathological context. Further, we and others have been able to adapt these screening technologies to live animals making it possible now to compare the effects of potential therapeutic drugs in cultured heterologous cells, cells derived from animals or patients, and whole animals. We propose here to test a key concept in modern drug development which aims to make drugs with fewer side effects by biasing them toward the required effects of a drug and away from the adverse effects. These concepts were developed in cell models but have not be rigorously been tested in animals. If we can establish whether these convenient cell culture-based models predict drug effects in living animals, this will greatly facilitate our ability to design and test better drugs.