Volker Lauschke

Volker Lauschke

Professor
E-postadress: volker.lauschke@ki.se
Telefon: +46852487711
Mobiltelefon: +46704926778
Besöksadress: Solnavägen 9, Biomedicum, 17165 Solna
Postadress: C3 Fysiologi och farmakologi, C3 FyFa Individanpassad medicin och läkemedelsutveckling, 171 77 Stockholm
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Artiklar

Alla övriga publikationer

Forskningsbidrag

  • Swedish Research Council
    1 December 2024 - 30 November 2027
    Primary human hepatocytes rapidly lose their functionality in conventional 2D cultures, which significantly limits their usefulness as an in vitro model to study hepatotoxicity, particularly of biological and nanoparticle therapeutics, which commonly accumulate and exert their effects over prolonged periods of time. Thus, in the absence of relevant in vitro systems, animal models constitute a cornerstone to predict the toxicity of newly developed biologics. The liver is however an organ with pronounced species differences with regards to expression and catalytic activities of factors involved in drug absorption, distribution, metabolism and excretion. This is further amplified for nucleotide- and antibody-based therapeutics where sequence and epitope differences between species are common problems during preclinical development.We have previously developed a 3D human liver model that accurately predicts the hepatotoxicity of small molecules, which is by now widely used in industry. Here, we aim to extend this work and develop and benchmark a platform that can predict hepatotoxicity and liver biodistribution of biologics (antisense oligonucleotides, siRNAs, therapeutic antibodies) and different nanoparticles (lipid-based, polymeric and inorganic). This system aspires to improve the predictability and translatability of findings as well as to mitigate the need for animal models, thus reducing the number of animals needed in pre-clinical discovery and development.
  • Swedish Research Council
    1 January 2024 - 31 December 2028
    Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons. NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH. NASH is closely linked to obesity, sarcopenia, dyslipidemia and insulin resistance and it has become clear that multiple extrahepatic tissues, including pancreas, skeletal muscle and adipose tissue produce signals that orchestrate hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans remain poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver, pancreas, skeletal muscle and fat to comprehensively map human metabolic crosstalk. By analyzing the secretome from healthy and diseased individuals, we will identify novel endocrine signals that contribute to NASH etiology and progression. Moreover, we will use the established platform to screen chemogenomic libraries to identify compounds that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.
  • Chemogenomic profiling of nuclear hormone receptors as targets for NASH
    Novo Nordisk Foundation
    1 November 2023 - 31 October 2025
    Non-alcoholic steatohepatitis (NASH) is a very common liver disease that affects around 1/3 of all obese persons worldwide. NASH is caused by buildup of fat in the liver, which results in inflammation and liver damage. Despite its prevalence, there are currently no approved treatments for NASH._x000D_ In this project we aim to facilitate the development of novel drugs against NASH by targeting a protein family called nuclear receptors (NRs). Specifically, we will culture liver cells isolated from NASH patients as 3D liver microtissues and treat those micro-livers with hundreds of different substances that specifically target NRs. This approach will allow us to directly identify which substances reduce fat buildup, inflammation or liver injury. Such “hit molecules” will then be validated in animal models of NASH and provide good candidates to finally develop effective treatments for this prevalent disease._x000D_
  • Swedish Research Council
    1 January 2023 - 31 December 2026
    The availability of relevant in vitro models of tissue units would be highly valuable for our struggles to understand human biology and physiology to obtain better health solutions. In the native tissue, cells are organized by a supporting extracellular matrix (ECM) in various types of microenvironments. ECM proteins build up the frameworks of these different environments, e.g. interstitial fiber networks in connective tissue and basement membranes in biological barriers. It has lately become clear that cells in culture are largely affected by their microenvironment, and especially mechanotransduction and the availability of cell-cell and cell-matrix connections. We will herein use a functionalised recombinant spider silk protein to construct relevant ECM-mimics, both networks for parenchymal and support cells in tissue compartments, and membranes for their biological barriers. These we will use to survey the effect of different parameters of the environment for cells in culture. For investigations of biological processes, it is essential to include a combination of cellular compartments and biological barriers. We will use our obtained knowledge to construct physiologically relevant tissue units of 1) tumours in stroma with blood vessels, for investigations of the interplay between cancer cells and vasculature, as well as 2) tumours behind blood brain barrier (BBB), for investigation of treatment strategies of brain tumours.
  • Deutsche Forschungsgemeinschaft
    1 January 2023
    Non-alcoholic steatohepatitis (NASH) is a serious liver disease characterized by fat accumulation, inflammation, and fibrosis. It affects ~6% of the global population but lacks effective treatment options and is thus a severe medical and healthcare challenge. Pharmacological treatment options are urgently needed to address this unmet medical need. Therapeutic modulation of nuclear receptors (NRs), many of which crucially regulate hepatic metabolism and inflammation, is increasingly recognized as potential avenue to hepatoprotective NASH treatment. However, only a minor fraction of the 48 human NRs has been evaluated in this context and comprehensive understanding of the entire NR family’s involvement in NASH pathology is lacking. Growing evidence supports remarkable potential of many (orphan) NRs to mediate beneficial therapeutic effects in NASH. For example, relevant sex-specific differences in NASH incidence point to an involvement of steroid hormones which act via NR activation. The role of hormone sensing and other NRs in the disease complex urgently requires systematic and comprehensive evaluation for therapeutic potential. This project aims to close this gap by systematically probing NR modulation for therapeutic effects in a primary patient-derived tissue model following a chemogenomics (CG) strategy. To meet its main objective of achieving comprehensive understanding of the pharmacological role of NRs in NASH, the project will assemble a custom CG compound set to cover ≥40 of the 48 human NRs and systematically assess the phenotypic outcomes of NR modulation in liver spheroids generated from primary human hepatocytes and non-parenchymal liver cells. Using such sophisticated in vitro model to mimic relevant disease characteristics aims to overcome incomplete translation from rodent model to patient in NASH and to capture individual and sex-specific differences. Primary evaluation will focus on anti-steatotic, anti-inflammatory, anti-fibrotic, and anti-oxidative effects in a global, sex-specific, and genotype-dependent manner. Subsequently, beneficial effects resulting from NR modulation will be orthogonally validated and analyzed in-depth for sex- and patient-specific roles, dependence on metabolic parameters, potential synergies of dual modulation, and signaling networks. This unprecedented systematic and comprehensive approach to explore NRs as therapeutic targets for NASH treatment will reveal uncharted potential of this protein family and address an urgent unmet medical need. Additionally, new insights into the roles of steroid hormones as well as sex- and patient-specific differences in NASH will offer significant biological advance and may suggest personalized treatment strategies.
  • Swedish Research Council
    1 January 2022 - 31 December 2025
    Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons. NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH. NASH is closely linked to obesity, dyslipidemia and insulin resistance and it has become clear that that the adipose tissue produces many signals that control hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans are poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver and fat to comprehensively map human fat-liver metabolic crosstalk. By analyzing the secretome of adipose tissue from lean insulin-sensitive and obese insulin-resistant individuals, we will identify novel endocrine signals of human fat that promote or prevent NASH. Moreover, we will use the established platform to screen libraries of lead-like molecules to identify compounds that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.
  • Swedish Research Council
    1 December 2019 - 31 December 2022
  • Swedish Research Council
    1 January 2017 - 31 December 2020
  • Swedish Research Council
    1 January 2017 - 31 December 2019
  • Swedish Research Council
    1 January 2016 - 31 December 2016

Anställningar

  • Professor, Fysiologi och farmakologi, Karolinska Institutet, 2023-

Examina och utbildning

  • Docent, Farmakologi, Karolinska Institutet, 2018

Handledning

  • Handledning till doktorsexamen

    • Jibbe Keulen
    • Chen Xing

Nyheter från KI

Kalenderhändelser från KI