Our long term goals are to understand the molecular interactions governing neuroimmunology and their relationship to infectious oral diseases, e.g., recurrent Herpes simplex virus infection, HIV and periodontal diseases, and wound healing: processes associated with stress and/or enhanced fluxes of catecholamines (CAs) and immune dysfunction. Previous studies by others and us demonstrated association between CAs and diminished immune function. These investigations focus on the hypothesis that the nervous system interacts with the immune system in part through the agency of CAs, sympathetic neurotransmitters most closely associated with immune cells and their reservoirs. This grant investigates specific molecular mechanisms involved in CA-mediated immune gene expression; in particular, the CA-mediated downregulation of mRNAs necessary for regulated Tcell function. To do this, we will use well characterized cloned murine cells of T cell lineage (S49 lymphosarcoma, EL-4 cells and a CD8+ cell line) to study the CA-mediated dynamics of mRNAs of genes associated with immune regulation (the Beta-adrenergic receptor and the cytokines TNFa, IL-2 and IFN-y) down-regulated by cAMP, the second messenger associated with CA-beta-adrenergic signaling.
Specific Aim I determines whether these genes are down-regulated by CA exclusively through mRNA destabilization or in concert with other mechanisms and continues investigation of our paradigm for mRNA destabilization that a (CA/cAMP/PKA) protein kinase mechanism is central to regulation of mRNA stability this Aim will a) identify the RNA target sites in CA/cAMP/PKA modulated mRNAs that affect their stability and b) investigate the mechanisms through which CAs modulate mRNA destabilization in T cells by characterizing the proteins that affect mRNA stability.
Specific Aim II will explore new data that suggest the hypothesis that CM modulates specific gene products involved in the activation and function of Herpes simplex (HSV) specific cytotoxic T lymphocytes. Completion of these Specific Aims provides insight into exciting and unique mechanisms whereby CAs down-modulate mRNAs for effector proteins of immune cells to decrease the capacity of these cells to respond to external signals and HSV infection and could allow development of peptides and oligonucleotide therapies designed to inhibit the effect of endogenous stressors and/or enhance immune function.
| LaJevic, Melissa D; Koduvayur, Sujatha P; Caffrey, Veronique et al. (2010) Thy-1 mRNA destabilization by norepinephrine a 3' UTR cAMP responsive decay element and involves RNA binding proteins. Brain Behav Immun 24:1078-88 |
