Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disorder of indeterminate etiology with multiple immune effector dysfunctions, which afflicts females in the child bearing years. Protein kinase A (PKA) plays an important role in regulation of immune effect functions of T cells. Our previous research has revealed a disorder of type I protein kinase A (PKA-I) enzyme activity in SLE T cells. Recently I have identified mRNA transcript editing of PKA-1 RIalpha-subunit in SLE T cells. The RNA editing is the co- or post-transcriptional modification of RNA molecules, which results in the insertion, or substitution of nucleotides. MRNA editing plays an important role in the regulation of gene expression and produces phenotypic variability by diversifying the information encoded within the corresponding genomic sequence. The objective of this proposal is to identify the molecular mechanism(s) leading to mRNA transcript editing in RIalpha- and RIbeta-subunits of PKA-I and their role in deficient PKA-I isozyme phosphotransferase activity in SLE T lymphocytes.
The specific aims of the project are: (1) to determine and quantify the mRNA transcript editing in RIalpha- and RIBETA-subunit gene transcripts and its role in deficient PKA-I isozyme of dsRNA adenosine deaminase (dsRAD) genes in SLE T cells and their role in editing of RIALPHA- and RIBETA-subunit gene transcripts by conversion of adenosine to inosine in PKA-I RIALPHA- and RIBETA-subunit gene transcripts of SLE T cells and the subsequent dissection of editing mechanisms. The novel data derived from these experiments will prove crucial in addressing questions of functional, biological, significance, and regulatory events responsible for deficient PKA-I isozyme phosphotransferase activity in SLE T lymphocytes. Identification of this new mechanism of transcript mutations will provide new insights into the mechanisms of abarrent T cell immune effector functions in SLE and open a new avenue of research to design molecular tools to control abarrant immune function
| Kammer, Gary M; Laxminarayana, Dama; Khan, Islam U (2004) Mechanisms of deficient type I protein kinase A activity in lupus T lymphocytes. Int Rev Immunol 23:225-44 |
| Laxminarayana, Dama; Khan, Islam U; Kammer, Gary (2002) Transcript mutations of the alpha regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes. Lancet 360:842-9 |
