Atherosclerosis (athero) is a major cause of death in the US but is mitigated by lowering plasma lipids. Major progress has been made to lower plasma lipids with statins, lomitapide, and mipomersen. However, (1) many patients are intolerant to statins, and (2) both lomitapide and mipomersen cause hepatic steatosis and are only approved for familial hypercholesterolemia (FH) patients who have defective LDL receptors (LDRs). Thus, there is a need to find new and safe drugs that can reduce hypercholesterolemia and athero without causing side effects. Our lab has shown that lentiviral-mediated hepatic expression of miR-30c reduces plasma lipids and athero in Western diet fed mice without causing hepatosteatosis. In contrast, inhibition of miR-30c increases plasma cholesterol and athero, indicating that endogenous miR-30c regulates plasma lipids. As virus mediated therapy is formidable in humans, I tested a stabilized miR-30c mimic, and, thus far, have reproduced the effects we saw with the viral vectors. Based on these data, I hypothesize that (1) miR-30c mimic might treat hypercholesterolemia and athero without causing steatosis, and (2) miR-30c is a regulator of plasma and tissue lipid metabolism.Aim 1: Treating hypercholesterolemia in mice: (a) I will test the hypothesis that hepatic overexpression of miR-30c will reduce plasma cholesterol, retard the progression of athero, and regress established atherosclerotic plaques in Ldlr-/- mice fed a Western diet. (b) I propose that miR-30c mimic (1) reduces plasma lipids by reducing VLDL production and MTP expression, and (2) decreases de novo lipogenesis and LPGAT1 expression to avoid steatosis. (c) I will determine whether miR-30c mimic will reduce apoB production in normal human primary hepatocytes, and in stem cell derived FH hepatocytes. Aim 2: Ablation of miR-30c genes causes hyperlipidemia: I hypothesize that single and double miR-30c-1-/- and miR-30c-2-/- knockout (KO) mice will have increased MTP levels and elevated plasma lipids when fed chow and Western diets. Further, they will develop steatosis due to increased LPGAT1 expression and de novo lipogenesis.These studies will (1) provide ample evidence to support the proof of concept that miR-30c mimic can be used as a beneficial treatment modality for hypercholesterolemia and athero in mice and (2) show that both the miR-30c genes play key roles in modulating plasma lipid levels and hepatic and intestinal lipoprotein production.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2016 → 12/31/2017|