BLRD Research Career Scientist Award Application

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications & trials

Abstract

Summary Our Veteran population has a significantly higher prevalence of diabetes mellitus and faces an increased risk of developing cardiovascular diseases (CVD) as compared to the general population. Stringent guidelines recommend decreasing plasma LDL-cholesterol to very low levels in patients with high risk for atherosclerosis and other cholesterol-related disorders. However, achieving these goals and reaching the targeted low LDL cholesterol levels in high-risk patients remains challenging. Thus, novel and superior therapeutic interventions are warranted to manage hypercholesterolemia in patients with high risk for CVDs. Over the past 20 years, my studies have primarily focused on investigating the roles of gut-related mechanisms in maintaining cholesterol homeostasis in the body to effectively manage hypercholesterolemia and associated diseases. Specifically, our studies were centered on the intestinal handling of cholesterol and bile acids and the effects of targeting these intestinal pathways on metabolic dysfunction, liver diseases, and gut disorders. Our studies have yielded several novel mechanistic insights regulating intestinal cholesterol transporter NPC1L1. We were the first to show that NPC1L1 expression in the intestine is sensitive to alterations in epigenetic modifications such as DNA methylation. Further, we have generated a novel transgenic mouse with intestine-specific overexpression of SREBP2, which provides a unique tool to examine the contributions of the intestine to cholesterol homeostasis. Our studies showed that 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 intestinal NPC1L1 cholesterol transporter mediates the infection with the hepatitis C virus. These studies resulted in an invention: New Indication for Ezetimibe and other NPC1L1-inhibitors as a treatment for hepatitis C virus infection. 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. We have recently developed several state-of-the-art innovative methods, such as measuring bile acid transport in real-time and in living cells and click chemistry- based metabolic approaches using alkyne cholesterol to assess cholesterol absorption and transport. Ongoing studies in my laboratory demonstrated the differential effects of saturated vs. unsaturated fatty acids on the function of the intestinal bile acid transporter ASBT, potentially via the process of s-acylation. The regulatory roles of fatty acids in modulating bile acid absorption are novel and represent a molecular structure that could be targeted to treat hypercholesterolemia and liver disease effectively. Our future studies are directed at unraveling novel pathways encompassing gut-liver interaction in health and metabolic dysfunction, liver diseases, and gut disorders. My active involvement in teaching and education missions at the VA and the affiliate University complements my research interests. I have mentored many undergraduate students, graduate students, medical students, physician-scientists, and GI Fellows. Several of my trainees have received support through the NIH's post-doctoral F32 and predoctoral F30 training grant mechanism. I am currently an MPI on a T35 grant from the NIH to continue mentoring and supporting medical students' research at the early stages of their education. Furthermore, my research program has established robust collaborations with VA-based investigators across multiple disciplines, aligning with the VA's mission to advance research to improve our veterans' health. Given the significantly higher risk of CVD in veterans compared to the general population, my research program's pursuit of novel methods to lower plasma cholesterol is both timely and critically relevant to the health of our veterans, especially those with diabetes mellitus.