https://umr1087.univ-nantes.fr/medias/photo/foto_1667558761555-jpg
  • Le 13 January 2023
    Amphi Denis Escande
    false false
  • 11h30

From phenotypes and shared genes to therapy - Using integrated multi-omics for precision therapy of metabolic disorders

From phenotypes and shared genes to therapy
Using integrated multi-omics for precision therapy of metabolic disorders 


Dr Carolin Schneider, MD, PhD
RWTH Aachen, Germany
Principal Investigator of Schneider Lab 2 and Internal Medicine Resident


Abstract

The global epidemic of obesity is paralleled by a massive rise in metabolic-associated fatty liver disease (MAFLD) and cardiovascular disorders (CVD). MAFLD, the most common liver disease, already affects 30-40% of the western population and is expected to become the primary cause of liver failure in Western nations. The pathophysiological hallmark of MAFLD is excess lipid accumulation in the liver. Steatosis is strongly influenced by genetics, and the best established MAFLD-related genetic risk variants TM6SF2 rs58542926 (E167K) and PNPLA3 rs738409 (I148M) both lead to increased hepatocellular lipid accumulation. Since hepatic lipid metabolism and plasma lipoprotein metabolism are so tightly interconnected, pharmacological treatment of steatosis may have an impact on plasma lipids, and vice versa. Overexpression of TM6SF2, for example, decreases steatosis by increasing very-low-density lipoprotein (VLDL) secretion and consequently plasma lipid levels; conversely, approved medications that lower low-density lipoprotein (LDL) cholesterol by reducing hepatic VLDL secretion exacerbate hepatic steatosis. This necessitates the development of novel system-level approaches to uncover new therapeutic targets for hepatic steatosis without increasing plasma lipids and thus CVD risk. The ideal target for MAFLD therapy would reduce hepatic lipid accumulation and hence the risk of MAFLD while having no effect on (or even reducing) serum lipid levels. 
 

Biography

My fascination for the interaction of genetics, environment and between liver and fat metabolism was initiated during my medical doctoral thesis on the effect of the Z mutation in SERPINA1 on liver and fat metabolism under the supervision of Prof. Pavel Strnad.  During my time in Prof. Strnad's  lab, I began to work on the detailed phenotyping of common genetic variants.  My primary goal as a patient-centric scientist is to provide my patients with better diagnostic and treatment options. I am interested in finding ways to reduce the burden of metabolically associated fatty liver disease (MAFLD) and its complications. Therefore, after my exam in December 2019, I decided to join a "Postdoctoral Fellowship" in the US. To expand my knowledge in translational clinical research with a particular focus on biostatistics and data science, I decided to join the group of Professor Rader, who is the Chair of the Department of Genetics, Deputy Director of the Institute of Translational Medicine and Therapeutics (ITMAT), Head of Translational Medicine and Human Genetics, and Principal Investigator at the Penn Medicine Biobank at UPENN, US.
During my postdoc, my projects dealt with common genetic variants and their influence on changes in hepatic lipid metabolism.  My long-term goal was to understand the molecular lipid-associated signaling pathways that contribute to MAFLD by studying genetic variants, allowing us to develop interventional strategies and thereby avoid major complications of MAFLD.  After 3 years of postdoc at UPENN, I started my own lab in July 2022  focussing on using genetic variants to find therapeutic targets for metabolic diseases.