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 effector functions of T cells. Previous research has revealed a disorder of type I protein kinase A (PKA-I) enzyme activity in SLE T cells. Recently the applicant has identified mRNA transcript editing of PKA-I RIalpha-subunit and up-regulation of the transcript editing gene, adesosine deaminases that acts on RNA (ADAR) in SLE T lymphocytes. The RNA editing is the co- or post-transcriptional modification of RNA molecules, which results in the insertion, deletion 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 quantify mRNA transcript editing in RIa and RIbeta gene transcripts in T cells from patients with SLE and compare this with normal controls as well as patients with rheumatoid arthritis (RA) to characterize its association with SLE pathogenesis;(2) to characterize mutant RIa- and Ribeta-subunit proteins phosphotransferase activity in T cells from SLE patients;(3) to analyze regulation and expression of the ADAR gene in T cells from normal, RA and SLE patients and determine whether there is a selective association with SLE pathogenesis;(4) to quantify ADAR-mediated adenosine to inosine conversion in controls and SLE lymphocyte gene transcripts; and, (5) to quantify ADAR2 transcript editing in T cells of SLE patients and compare this with that in T cells of normals and RA patients to characterize its association with SLE pathogenesis. Therefore, the major goal of this project is to identify RNA editing events in the 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 aberrant T cell immune effector functions in SLE and open a new avenue of research to design molecular tools to control aberrant immune functions.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Mancini, Marie
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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Orlowski, Robert J; O'Rourke, Kenneth S; Olorenshaw, Irene et al. (2008) Altered editing in cyclic nucleotide phosphodiesterase 8A1 gene transcripts of systemic lupus erythematosus T lymphocytes. Immunology 125:408-19
Laxminarayana, Dama; Khan, Islam U; O'Rourke, Kenneth S et al. (2007) Induction of 150-kDa adenosine deaminase that acts on RNA (ADAR)-1 gene expression in normal T lymphocytes by anti-CD3-epsilon and anti-CD28. Immunology 122:623-33
Laxminarayana, Dama; O'Rourke, Kenneth S; Maas, Stefan et al. (2007) Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes. Immunology 121:359-69