Dr. Hilla Giladi, Ph.D. was staff scientist and lab manager at the Gene Therapy Institute. Here group studied the expression and the function of microRNAs, mainly of miR-122. Prof. Giladi group characterized the human miR-122 promoter region and demonstrated that it is enhanced by TNFα and LPS inflammatory signals, and we determined the structure of the miR-122 primary transcript which consists of three exons, the third of which gives rise to miR-122.
Administration of LPS to mice increased secretion of miR-122 that reached the kidney and reduced the expression of Erythropoietin (EPO) which we identified as a miR-122 target gene, leading to anemia.MiR-122 level was shown to be reduced in hepato-cellular-carcinoma (HCC) and addition of miR-122 was shown to induce tumor suppression. We found that miR-122*, the passenger strand of miR-122, contributes to the tumor suppression activity of miR-122 by regulating the expression of p53 via targeting of its regulator, Mdm2.
- In an attempt to enhance tumor suppression activity by microRNA molecules, we are searching for compounds that increase the expression and secretion of miR-122 and of an additional highly conserved microRNA, miR-34a, that also possesses tumor suppressor activity in multiple malignancies. We are presently analyzing several identified compounds that exhibited enhanced expression of each these microRNAs.
- To study in depth the role of each of the miR-122 strands, we engineered mice bearing mutations in either miR-122-3p or in miR-122-5p and we are investigating the effect on major processes, including cancer development.
- We identified a metabolic circuit involving Free Fatty Acid- miR-122 -Triglyceride synthesis, in liver and muscle tissue, and showed that miR-122 mediates the switch between energy storage and expenditure. The RAR related orphan receptor α (RORα) promotes expression of miR-122. We identified a novel RORα agonist that upregulates the expression of miR-122 and leads to attenuation of NAFLD ( Non-Alcoholic Fatty Liver Disease) in mice by affecting hepatic lipotoxicity, reversing liver fibrosis, improving insulin resistance and reducing body weight. Thus, RORα agonists may prove to be a promising novel treatment of NASH.
- RORα directly regulates the expression and secretion of FGF21. In mice and humans, acute and chronic pancreatitis is associated with a loss of FGF21 expression. We are assessing the endogenous expression of FGF21 by a RORα activator to determine its effect in treating acute pancreatitis.
In our lab we also investigated the role of the lncRNA (long non-coding RNA) H19 in carcinogenesis. Recently, we have found that miR-675, which is derived from the H19 transcript, regulates necroptosis in the liver by targeting FADD. This observation adds to the complexity of the effects of H19 in carcinogenesis.