Salivary Research and Immunomodulation Laboratory
Dr. Srinivasanâ€™s laboratory is interested in two broad areas of research:Â
Immune-mediated inflammatory disease (IMID) is an umbrella term that includes a group of ostensibly unrelated conditions that share common inflammatory pathways. IMID encompass diverse disorders such as rheumatoid arthritis, type 1 diabetes, periodontal diseases, inflammatory bowel disease and multiple sclerosis. Although the exact etiology is not known, most IMIDs are initiated when endogenous (self) or exogenous (pathogen associated) antigen/s trigger abnormal immune responses in susceptible individuals and mediate secretion of cytokines and other deleterious agents affecting any organ system and culminating in distinct pathology.
Research in Dr. Srinivasanâ€™s laboratory focuses on understanding the basis of immune-mediated inflammation in multiple autoimmune disease models. We hope to adopt knowledge derived from the mechanism of the IMID process to design novel therapeutics to target pathogenic T cells and suppress inflammation. While many different cell types may be involved, CD4+ T lymphocytes/helper cells are the main orchestrators of the immune response. Activation of T cells requires a primary signal delivered via the TCR-CD3 complex interacting with a MHC-peptide complex on an APC and a second costimulatory signal provided primarily by CD28 interacting with the B7 (CD80/CD86) molecules on the APC.Â Subsequent upregulation of CD152 on activated T cells, binds the B7 ligands on the APC, transmitting negative signals to terminate the immune response. B7/CD28:CD152 interactions play a critical role in the pathogenesis and/or regulation of autoimmune disease pathology. At the structural level, the autoimmune inflammation involves well-orchestrated low-affinity protein-protein interactions that regulate intercellular communications and intracellular signaling pathways. The binding between the B7:CD152 exhibits significantly higher affinity than the B7:28 interactions. Structurally, the CD28/CD152 receptor and the CD80/CD86 ligand are members of the immunoglobulin superfamily. Integrating these data with information from the structural complex of CD80:CD152 and CD86:CD152 we designed a unique peptide inhibitor, the CD80 competitive antagonistic peptide (CD80-CAP). Administration of CD80-CAP suppressed inflammation in experimental autoimmune encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease, and mouse models of multiple sclerosis, rheumatoid arthritis and colitis. Mechanistically, CD80-CAP suppressed Th1 cytokines and increased Th2 cytokines potentially by upregulating the expression of glucocorticoid induced leucine zipper (GILZ).
The anti-inflammatory and protection against activation-induced apoptosis mediated by glucocorticoids, widely used therapeutic agent in the management of autoimmune diseases, have been attributed to the induced upregulation of GILZ. Mechanistically GILZ acts by inhibiting NF-kB (p65) translocation and activation of pathological mediators. Structurally, GILZ:p65 interaction is mediated by the proline rich region of the carboxyl terminus of GILZ and the transactivation domain of p65. Recently we developed a rationally designed GILZ mimic which binds the p65 with low affinity, inhibits T cell responses and ameliorated disease in a mouse model of multiple sclerosis.
- To determine the roles of GILZ proteins in the activation and effector function of inflammatory cells, antigen presenting cells and neural cells.
- In-silico simulation and modeling of GILZ protein and small molecule inhibitor development.
Oral Fluids Research
Salivary Diagnostics: Over the last decade, saliva has gained considerable importance as a diagnostic fluid for predicting populations at risk for a variety of oral and systemic conditions. The clinical significance of salivary proteome, transcriptome and genetic markers have been explored for cancers of the oral cavity, breast and pancreas, for infectious diseases including hepatitis and acquired immune deficiency syndrome and for metabolic diseases such as diabetes and osteoporosis. Over the past five years, we have established a saliva bank that has over 100 unstimulated saliva samples from individuals with chronic oral mucosal lesions, periodontitis as well as healthy subjects. In addition to developing the biospecimen science with respect to saliva, my lab is interested in the identification and characterization of diagnostic/prognostic salivary biomarkers of oral and systemic diseases.
Our research primarily focuses on the role of innate immune responses, toll like receptor (TLR) in particular, in chronic oral inflammatory conditions such as lichen planus and periodontitis. We were one of the first labs to identify soluble TLR-2 and TLR-4 in the saliva and investigate its potential as a clinical biomarker for periodontitis.
- Characterization of epithelial cell expression of TLRs in relation to periodontopathic biofilm.
- Investigating potential functions of salivary sTLR-2 and sTLR-4.