The family of GTP-binding proteins, called G proteins, provides a signal transduction coupling mechanism for many cell surface receptors. The receptors act catalytically to mediate guanine nucleotide exchange at the GDP/GTP binding site of the G protein alpha subunit. This process is referred to as activation and results in the displacement of bound GDP for GTP. The GTP-bound form of the G protein then initiates a cellular response by altering the activity of specific enzymes or ion channels. The role of G proteins in specific diseases and pathological states has been implicated in many correlative studies in nervous, neuroendocrine and cardiovascular tissues. In two human diseases, pseudohypoparathyroidism and growth hormonesecreting adenomas, a direct correlation with a change in alphas expression or mutation has been demonstrated. Causative roles of G protein mutations in other diseases have not been directly demonstrated.
The aim of this proposal is to express dominant G protein mutants using gene transfer techniques to alter the regulation of effector enzymes including adenylyl cyclase and phospholipases C and A2. The consequence of constitutive stimulation or inhibition of G protein regulated effector enzyme systems will be defined in relation to changes in metabolism, transcription of specific genes and mitogenesis in fibroblasts, hepatomas and thyroid cells. These studies will characterize changes in cell function that result from altered G protein regulation of specific effector enzyme systems. In order to address the causitive role of altered regulation of adenylyl cyclase and phospholipases in disease, dominant G protein mutants will be expressed in the liver of transgenic mice. Changes in liver function will be determined and used as a model to define pathologies that develop from altered biochemical regulation of cell function resulting from the expression of G protein mutants in a selected tissue of the mouse. The long-term objective of our work is to provide a molecular understanding of the hormonal control of regulatory systems in mammalian tissues and the pathologies that develop when this control is lost. Progress in this area will help in developing animal models for specific diseases that involve G protein regulated pathways.
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