In envisioning how stem cells could be used to replace lacking or deficient cells in the central nervous system (CNS), we recognize that one of the best way would be to induce stem cells present in the brain to differentiate into the lacking or deficient cells. When considering Parkinson's disease, one of the best way to develop a therapy would be for mature neurons that can replace lacking dopamine-expressing cells. The issue is how to drive stem cells into becoming full-fledged neurons. This project proposes a new way at reaching this goal.
Every cell in the organism expresses a battery of G protein-coupled receptors (GPCRs). The GPCRs bind all the small molecules that direct intercellular interactions. Importantly these include all the neurotransmitters and neuropeptides., making the GPCRs the prominent regulators of brain function. Binding of the GPCR ligands initiate a cascade of intracellular reactions that change the transcriptional activity of the recipient cell. Most notably GPCR activation can initiate differentiation, i.e. they may be able to induce a stem cell to become a neuron.
Each cell in the organism, expresses a few dozen different GPCRs. Although not determined thus far, stem cells too will harbor several GPCRs, probably at least as many as the adult cells. If we can find the stem cells GPCRs we may be able to use them to transformed these cells into neurons. The first issue is to find all the stem cells GPCRs. This will be done using a well developed technique, RT-PCR. Using it we will catalog all the GPCRs express in different stem cells.
We will then activate the GPCRs that we have found on stem cells to determine whether they can induce the stem cells to differentiate into neurons. There are already data that a few GPCRs have this ability. Our aim will be to discover how many can do it and whether there is some commonalities between the ones that have this ability. We will also determine whether the exhibit differences in the neuronal phenotypes and thus define the cascade of events that leads to this phenotype.
Knowing which GPCRs can induce neuronal phenotypes and at which step in the differentiation process a particular GPCR acts will have direct impact on therapies. GPCRs are the most sought targets in drug development and many drugs acting on GPCRs already exist. Our research may point at some of these drugs as potential mediators of neuronal regeneration and possibly helpers in therapies aiming at replacing lacking neurons.
Statement of Benefit to California:
The success of this proposal would have a positive outcome for California. It approaches the use of stem cells from a pharmacological stand point. In doing so it leads to therapies that do not require surgical intervention. Instead it may point at existing drugs as potential agents for neuronal regeneration. This would result in immediate applications. It may also point at new targets that should be pursued pharmaceutically.