The long term goal is to increase understanding of molecular mechanisms involved in development and maintenance of the nervous system, and how perturbations of these processes might be involved in certain disease states, especially inherited diseases and age-related disorders. The focus of the research is on S100beta, a glial cell protein that has neurotrophic activity; i.e., S100beta can selectively stimulate neurite outgrowth and enhance survival of CNS neurons. Feasibility data indicate that S100beta also stimulates glial cell proliferation. Thus, S100beta may be involved in the coordinate development and maintenance of the CNS by synchronously stimulating the differentiation of neurons and the proliferation of glia. However, nothing is known about the mechanisms which enable these cell types to respond differentially to S100beta. It is the goal of this proposal to fill a void in our knowledge of the molecular mechanisms by which S100beta stimulates glial cell proliferation. The two questions being addressed are: 1. what are the characteristics of the cell surface components that recognize S100beta; i.e. the receptor? and 2. how does binding of S100beta bring about stimulation of cell proliferation; i.e., signal transduction pathways? By addressing these two mechanistically coupled questions, insight will be gained into how molecular recognition of S100beta by the glial cell is transduced through intracellular signal transduction events to the eventual proliferative response. These studies will provide the necessary knowledge to pursue longer-term studies aimed at probing molecular mechanisms at a more detailed level, in order to understand how the cell surface events are coupled mechanistically to the nuclear events (changes in gene expression) and vice versa, and what distinguishing features of these pathways determine the specific biological responses of glial vs neuronal cells to S100beta stimulation. This research also has the potential to increase understanding of the neuropathologies associated with age-related disorders such as Down syndrome and Alzheimer's disease. Clearly, because S100beta can affect both glial and neuronal cells, aberrant S100beta gene expression and protein production/targeting during critical periods of development could have profound effects on nervous system function. In this regard, the abnormally high levels of S100beta found in the brains of patients with these diseases may be linked directly to the observed gliosis and abnormal neuritic outgrowth, and to the cascade of neuropathological events that with aging lead to mental retardation and dementia. This research has the potential to provide the basic knowledge necessary for future approaches to diagnostics and therapeutics for these age-related disorders.
| Hu, J; Castets, F; Guevara, J L et al. (1996) S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biol Chem 271:2543-7 |
| Hu, J; Van Eldik, L J (1996) S100 beta induces apoptotic cell death in cultured astrocytes via a nitric oxide-dependent pathway. Biochim Biophys Acta 1313:239-45 |
| Lin, L H; Van Eldik, L J; Osheroff, N et al. (1994) Inhibition of protein kinase C- and casein kinase II-mediated phosphorylation of GAP-43 by S100 beta. Brain Res Mol Brain Res 25:297-304 |
