The major goal of this project is to elucidate the mechanisms of non- genomic steroid effects in T lymphocytes. Non-genomic steroid actions have received much attention in the past decade. They are characterized by their rapid onset of action and by being independent of transcription and protein synthesis. Non-genomic steroid actions are ubiquitous and well documented. Steroid hormones have been shown by us and others to cause rapid changes in calcium signals in lymphocytes. These changes fall into the category of non- genomic steroid effects. In lymphocytes, initial calcium signaling upon TCR activation has been shown to occur by a two step process involving IP3 mediated release of calcium from internal stores and calcium influx through Ca2+ release-activated Ca2+ channels. This signaling cascade has been associated to tyrosine kinases in lipid rafts. Lipid rafts, or detergent insoluble microdomains, are surface membrane constituents that play important roles in signal transduction and membrane trafficking in lymphocytes and many other cells. We propose that non-genomic steroid actions are mediated by steroid association to the proteins of the lipid raft.
The Specific Aims to be followed are:
Specific Aim 1 : Evaluate the non-genomic effects of the gonadal steroids on intracellular free Ca2+ levels in murine and human lymphoblastoid cell lines.
Specific Aim 2 : Determine the presence of caveolae and/or detergent insoluble microdomains (lipid rafts) in lymphoblastoid cell lines.
Specific Aim 3 : Correlate the presenc3e of caveolae and/or lipid rafts in l in lymphocytes with the non-genomic action of gonadal steroids on Ca2+ signaling. The results obtained in this project will contribute to our understanding of the cellular and subcellular mechanisms involved in signal transduction, non-genomic steroid action and for our understanding of the mechanisms involved in immunosuppression.
Showing the most recent 10 out of 51 publications
