Background:
MicroRNAs (miRNAs) are small non-coding RNA molecules encoded by eukaryotic nuclear DNA, on average 22 nucleotides long, that function in transcriptional and post-transcriptional regulation of gene expression via base-pairing with complementary sequences within mRNA molecules, usually resulting in gene silencing via translational repression or target degradation. Aberrant expression of miRNAs has been implicated in numerous disease states including sepsis (Wang et. al. PLoS ONE, 2012, 7(6):e38885). Sepsis is a leading cause of death worldwide, characterized by an overwhelming systemic inflammatory response to infection. The uncontrolled release of inflammatory mediators (i.e. TNF-alpha) results in apoptosis/necrosis of cells/tissues and microvascular dysfunction that contribute to multiple organ failure and ultimately death in 30-50% of patients. Abrogation of inflammatory mediators and apoptosis to protect cells/tissues/organs is a promising therapeutic strategy for sepsis.
Description of the Invention:
Down-regulation of anti-apoptotic proteins promotes apoptotic cell death significantly contributing to sepsis-associated organ dysfunction. Our researchers have previously demonstrated that miR-195 expression promotes apoptosis in cardiomyocytes through targeting and down-regulation of the anti-apoptotic protein Sirt1 (Zhu et. al. Cardiovascular Research, 2011, 92:75-84). Our researchers have now demonstrated in two different animal models of sepsis (LPS-induced; FIP (feces-in-peritoneum)-induced) that inhibition of miR-195 not only prevents apoptosis, but also significantly reduces inflammation and prevents multiple organ dysfunctions (liver, kidney, lung) during sepsis. Decreased apoptosis of endothelial cells (as indicated by TUNEL and caspase-3 assays) were evident in liver, kidney and lung protecting the vasculature and attenuating microvascular dysfunction. Inflammation was significantly decreased in liver, kidney and lung as evident through decreased levels of myeloperoxidase (MPO) activity and inflammatory mediators (iNOS; TNF-alpha). Functional tests indicate significant protection and preservation of liver (ALT & AST) and kidney (BUN) organ function during sepsis. The combined results indicate that inhibition of miR-195 is a promising therapeutic approach for sepsis.
Potential Advantages/Applications:
• miR-15 family member inhibition (i.e. miR-195) reduces apoptosis, inflammation and microvascular dysfunction apoptosis to protect and preserve multiple organ function (liver, kidney, lung) during sepsis.
