Thursday, April 18, 2024
4/18/2024
Project Summary Atherosclerosis is initiated and promoted by the arterial accumulation of apolipoprotein B (apoB)-containing lipoproteins which activate a chronic inflammatory response. The hepatocyte is the major source of apoB- lipoprotein particles via its ability to secrete very-low-density lipoprotein (VLDL), which is then hydrolyzed into intermediate-density lipoprotein (IDL) and then low-density lipoprotein (LDL) in the blood. We recently discovered that a key blood clot lysis protein, tissue-type plasminogen activator (tPA), in hepatocytes limits the production of apoB-lipoproteins in mice and cultured primary hepatocytes. The overarching goal of the Parent R01 proposal is to explore the underlying mechanisms by which hepatocyte tPA lowers plasma apoB-containing lipoprotein- cholesterol levels. Our hypothesis is that hepatocyte tPA limits hepatic VLDL lipidation while increasing apoB- VLDL intracellular degradation prior to secretion. The therapeutic impact of this proposal is that increasing hepatocyte tPA in dyslipidemic mice has the potential to reduce atherogenic apoB-lipoproteins and atherosclerosis without raising the risk of fatty liver disease. Ms. Maya Rodriguez is a research technologist and a postbac trainee recently graduated from college. She is pursuing a career as a physician scientist and has been learning research with scientists involved in the Parent R01. We have formed a mentoring team and developed a thoughtful plan for mentoring her to increase her research capacity and advance her career development toward her goal as a physician scientist. The PI of the Parent R01, Dr. Ze Zheng will be her primary mentor, and Dr. Roy Silverstein will serve as her co-mentor. Dr. Wen Dai (Research Scientist) and Hayley Lund (Lab Manager) will teach and assist Ms. Rodriguez's research. The goal is to teach Ms. Rodriguez how to contribute intellectually to the research, and to enhance her research skills and knowledge in thrombotic cardiovascular diseases. We are confident that, with our thoughtful mentoring plan, Maya will become even more competitive to reach her goal in the next stage of her career, i.e., become a physician scientist through the MSTP programs. We have developed a feasible research plan based on her interest and experience with a timeline that can be finished within two years before she goes to medical school and MSTP. Recent studies by Maya and others in our lab used clinical data analyses and found dyslipidemia is associated with thrombosis and impaired fibrinolysis in COVID-19, with mechanisms unclear. The original ideas of these clinical studies in COVID-19 were developed from the parent R01 study that tPA reduces VLDL secretion and tPA directly interacts with apoB (Wen Dai, et al, Science, 2023, in press). In this supplement award, Ms. Rodriguez proposes to investigate the potential mechanism by which tPA and PAI1 regulate lipid metabolism with the impact from immunological stimuli. This will be a logical extension to the Aim 3 of the parent R01, to determine whether increasing hepatocyte tPA in dyslipidemia reduces atherogenic cholesterol and atherosclerosis, without raising the risk of fatty liver disease.
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