BLRD Research Career Scientist Award Application

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Summary Our Veteran population has higher prevalence of diabetes mellitus and increased risk for developing cardiovascular diseases (CVD) as compared to general population. Since diabetes is generally associated with hypercholesterolemia, aggressive lowering of plasma LDL-cholesterol (<100mg/dL) is recommended for diabetic patients. Achieving these stringent goals and reaching the targeted low LDL cholesterol levels in high risk patients remains challenging. Thus, novel and superior therapeutic intervention is warranted to manage hypercholesterolemia in patients with high risk for CVDs. Over the past 15 years, my studies have primarily focused on investigating the roles of the gut in the maintenance of cholesterol homeostasis in the body with a goal to effectively manage hypercholesterolemia and associated diseases. Our studies have yielded several novel mechanistic insights in regulation of intestinal cholesterol transporter NPC1L1. The increase in NPC1L1 expression in diseases such as diabetes mellitus enhances cholesterol absorption and contributes to the associated hypercholesterolemia. Zetia (ezetimibe), the drug which inhibits NPC1L1 activity, decreases cholesterol levels in the blood. However, recent studies supported the principle of “the lower is better” for plasma cholesterol. Since ezetimibe only blocks NPC1L1 activity, decreasing NPC1L1 expression along with ezetimibe represents an attractive therapeutic approach for a further reduction in plasma cholesterol. In this regard, our studies were first of its kind to identify two Sterol Response Elements in the NPC1L1 promoter sequence and showed that NPC1L1 expression is increased by the Sterol Response Element Binding Protein SREBP2. We have also recently shown that NPC1L1 expression in the intestine is sensitive to alterations in DNA methylation. Further, we have generated a novel transgenic mouse with intestine-specific overexpression of SREBP2 that represents a unique tool to examine the contributions of the intestine to cholesterol homeostasis. Our studies showed that this the activation of SREBP2 in the intestine only was sufficient to induce hypercholesterolemia and increased susceptibility to diet-induced liver injury. Our studies also demonstrated an increase in the stemness of intestinal epithelial cells by the overactivation of SREBP2. Our group contributed to the studies that led to a breakthrough discovery showing that NPC1L1 cholesterol transporter mediates the infection with hepatitis C virus. These studies resulted in an invention: New Indication for Ezetimibe and other NPC1L1- inhibitors as treatment for hepatitis C virus infection. Our studies pertaining to investigating intestinal cholesterol absorption have been continuously funded by a Merit Review grant from the VA since 2009. Ongoing studies in the laboratory are also focused on investigating the molecular regulation of ileal bile acid absorption and the contribution of its deregulation to the development of liver diseases (funded by R01 from NIH). Recently, we have developed several state-of-the art innovative methods such as measuring bile acid transport in real time and in living cells as well as click chemistry based metabolic approached using alkyne cholesterol. Our future studies are directed at unraveling novel pathways encompassing gut-liver interaction in health and metabolic diseases. My research interests are very well complemented by my active involvement in teaching and education mission at the VA as well as at the affiliate University. I have mentored a number of undergrad and grad students, physician scientists, GI Fellows and I am also the primary mentor on F30 predoctoral fellowship for VA based MD/PhD candidate (F30 DK117535). My research program has established strong active collaborations with other VA based investigators from multiple disciplines that align with the mission of VA in advancing the research for the care of our veterans. Notably, the risk for CVD is significantly higher in veterans as compared to the general population. Therefore, my research program to find novel means to decrease plasma cholesterol is timely and directly relevant to the health of veterans in general and, particularly, veterans with diabetes mellitus.