Autoimmune Sj""""""""gren's syndrome (SjS) targets the exocrine glands, such as the salivary and lacrimal glands, of mostly female individuals, leading to severe secretory dysfunction and its complications. To date, SjS- specific diagnostics and therapeutics have not been available due to complexity of SjS disease pathogenesis. MicroRNAs (miRNAs) have been recognized as an important class of non-coding RNAs that are involved in a variety of biological, pathological, and immunological processes. Our latest findings on altered miR-146a and- 155 expression in peripheral blood mononuclear cells (PBMC) or monocytes of primary SjS (pSjS) patients in comparison with healthy controls indicate that miRNAs may play a critical role in autoimmune initiation and progression of SjS. The data were further supported by the findings in the salivary glands and PBMC of our pSjS-prone C57BL/6.NOD-Aec1Aec2 mouse model, where up-regulation of those miRNAs was observed from an early age on. Over-expression of miR-146a in human monocyte cell line (THP-1) was able to alter innate immune responses such as phagocytosis and pro-inflammatory cytokine production in our preliminary study in vitro. We now propose studies designed to test our hypotheses that miR-146a and miR-155 are vital to prolong inflammatory processes by altering innate immune response and that pSjS-specific miRNAs especially involved in innate immunity can be differentially expressed (potentially even prior to disease onset resulting in persistent inflammation).
In Aim 1 of this project, we will investigate consequences of altered miR-146a and/or miR-155 by utilizing miRNA mimics and inhibitors transfected into THP-1 cells followed by functional assays. Altered functions will also be tested in primary cultured monocytes from pSjS patients.
This aim i s to determine if epigenetic regulation of immune genes by miRNAs are critical in altering immunological processes in SjS.
In Aim 2, we will begin to profile a complex network of miRNAs involved in pSiS by utilizing a miRNA microarray approach. Here we will test our hypothesis that miRNA profiles that are specific for human pSjS are identifiable. Furthermore, we will continue to identify in Aim 2 target genes of differentially expressed miRNAs and perform functional assays established in Aim 1 to screen their involvement in innate immune responses. We envision that these experiments will identify novel miRNAs in pSjS and regulatory functions of identified miRNAs in abnormal immune regulation of SjS and may ultimately be amenable to development of biomarkers and therapeutic intervention.
Sjgren's syndrome (SjS) affects 4 million Americans, resulting in dry mouth and dry eye condition in patients. Our research proposal to identify SjS-specific profiles would advance diagnostics and therapeutics in the field and improve quality of life in those affected with the disease.
|Zuo, Jian; Williams, Adrienne E G; Park, Yun-Jong et al. (2016) Muscarinic type 3 receptor autoantibodies are associated with anti-SSA/Ro autoantibodies in SjÃ¶gren's syndrome. J Immunol Methods 437:28-36|
|Williams, Adrienne E G; Choi, Kevin; Chan, Annie L et al. (2016) SjÃ¶gren's syndrome-associated microRNAs in CD14(+) monocytes unveils targeted TGFÎ² signaling. Arthritis Res Ther 18:95|
|Park, Yun-Jong; Cha, Seunghee; Park, Young-Seok (2016) Regenerative Applications Using Tooth Derived Stem Cells in Other Than Tooth Regeneration: A Literature Review. Stem Cells Int 2016:9305986|
|Nayar, Gautam; Gauna, Adrienne; Chukkapalli, Sasanka et al. (2016) Polymicrobial infection alter inflammatory microRNA in rat salivary glands during periodontal disease. Anaerobe 38:70-5|
|Shin, Yong-Hwan; Kim, Minkyoung; Kim, Nahyun et al. (2015) Epigenetic alteration of the purinergic type 7 receptor in salivary epithelial cells. Biochem Biophys Res Commun 466:704-10|
|Gauna, Adrienne E; Park, Yun-Jong; Nayar, Gautam et al. (2015) Dysregulated co-stimulatory molecule expression in a SjÃ¶gren's syndrome mouse model with potential implications by microRNA-146a. Mol Immunol 68:606-16|
|Kim, Hong-Kyun; Woo, Kyung Mi; Shon, Won-Jun et al. (2015) Comparison of peri-implant bone formation around injection-molded and machined surface zirconia implants in rabbit tibiae. Dent Mater J 34:508-15|
|Park, Young-Seok; Gauna, Adrienne E; Cha, Seunghee (2015) Mouse Models of Primary Sjogren's Syndrome. Curr Pharm Des 21:2350-64|
|Park, Yun-Jong; Koh, Jin; Gauna, Adrienne E et al. (2014) Identification of regulatory factors for mesenchymal stem cell-derived salivary epithelial cells in a co-culture system. PLoS One 9:e112158|
|Gauna, Adrienne E; Cha, Seunghee (2014) Akt2 deficiency as a therapeutic strategy protects against acute lung injury. Immunotherapy 6:377-80|
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