AG Carrier


Name: Prof. Dr. Lucie Carrier, PhD
Clinic/Institute: Institute of Experimental Pharmacology and Toxicology
Email: l.carrier@uke.de
Phone: +49 (0) 40 7410 - 57208

Research Focus and Main research questions

Functional Genomics of Inherited Cardiomyopathies:
Our projects aim at deciphering the contribution of microtubule modifications, ubiquitin-proteasome system and autophagy-lysosomal pathway in inherited cardiomyopathies and to test drug- and nucleic acid-based therapy options. Our main questions are:

  • Do sarcomeric mutations alter contractile and electrophysiological phenotype of human induced-pluripotent stem cell (iPSC)-derived cardiomyocytes and engineered heart tissues (EHTs)? Can we specifically target functional alterations with drug- and nucleic acid therapy as personalised medicine?
  • Do human iPSC-derived cellular models of modified microtubules develop functional alterations in EHTs? What is the impact of modified microtubules on the transport of autophagosomes, lysosomes and mitochondria? Can we improve autophagic flux and/or proteasomal activities by targeting microtubule modification? What is the impact of targeting microtubule modifications in mouse and human cellular models of hypertrophic cardiomyopathy?
  • How to reduce proteotoxicity in mouse and human iPSC-derived cellular models of desmin-related cardiomyopathy?

  • Materials
  • Materials

    Materials:

    • Mouse models of cardiomyopathy (Mybpc3-targeted knock-out and knock-in, CryabR120G)
    • Reporter mice for autophagy-lysosomal pathway (GFP-LC3)
    • Several adeno-associated virus vectors (UKE-HEXT virus facility in IEPT)
    • Stable HEK293 cells (reporter of the proteolytic systems)
    • Human iPSC bank from 20 patients with inherited cardiomyopathy
    • Isogenic controls of patient-specific iPSC lines (repaired cell lines created with CRISPR/Cas9 genetic tools)
    • Human iPSC models of modified microtubules created with CRISPR/Cas9 and isogenic control
    • Human CRYABR120G iPSC line created with CRISPR/Cas9 and isogenic control
    • 2D-culture of human iPSC-derived cardiomyocytes
    • Human iPSC-derived EHTs

  • Methods:

    • Zeiss Confocal microscope
    • Nikon Live cell Imaging plus spinning disk
    • Nanostring nCounter technology (UKE core facilities)
    • Methods of molecular biology (Cloning, Western-blot, RTqPCR on Taqman, …)
    • IonOptix system (contraction and calcium transient in intact adult mouse cardiomyocytes)
    • Echocardiography for rodents (Vevo 3100 system)
    • Maintenance of human iPSC lines
    • Cardiomyocyte differentiation from human iPSC lines (2 methods)
    • Measurements of force amplitude and kinetics of EHTs
    • Hollow posts with different stiffness for afterload-force relationships in EHTs
    • Frank-Starling mechanism
    • Force-calcium relationship in skinned EHTs on Aurora system

  • Publications:

    1. Wenzel K, Krämer E, Geertz B, Carrier L, Felix SB, Könemann S, Schlossarek S (2021) A transgenic mouse model of eccentric left ventricular hypertrophy with preserved ejection fraction exhibits alterations in the autophagy-lysosomal pathway. Front Physiol, in press.

    2. Kuhn C, Menke M, Senger M, Mack C, Dierck F, Hille S, Schmidt I, Brunke G, Bünger P, Schmiedel N, Will R, Sossalla S, Frank D, Eschenhagen T, Carrier L, Lüllmann-Rauch R, Rangrez AY, Frey N (2021) FYCO1 regulates cardiac autophagy and prevents heart failure due to pressure overload in vivo. JACC Basic Transl Med, in press.

    3. Rieblinger B, Sid H, Duda D, Bozoglu T, Klinger R, Schlickenrieder A, Lengyel K, Flisikowski K, Flisikowska T, Simm N, Grodziecki A, Perleberg C, Bähr A, Carrier L, Kurome M, Zakhartchenko V, Kessler B, Wolf E, Kettler L, Luksch H, Hagag IT, Wise D, Kaufman J, Kaufer BB, Kupatt C, Schnieke A, Schusser B (2021) Cas9-expressing chickens and pigs as resources for genome editing in livestock. Proc Natl Acad Sci U S A 118(10):e2022562118. doi: 10.1073/pnas.2022562118. PMID: 33658378

    4. Schuldt M, Pei K, Harakalova M, Dorsch LM, Schlossarek S, Mokry M, Knol JC, Pham TV, Schelfhorst T, Piersma SR, dos Remedios C, Dalinghaus M, Michels M, Asselbergs FW, Moutin MJ, Carrier L, Jimenez CR, van der Velden J, Duster DWD (2021) Proteomic and functional studies reveal detyrosinated tubulin as treatment target in sarcomere mutation-induced hypertrophic cardiomyopathy. Circ Heart Fail Jan 12: CIRCHEARTFAILURE120007022. doi: 10.1161/CIRCHEARTFAILURE.120.007022. Online ahead of print. PMID: 33430602.

    5. Carrier L (2021) Targeting the population for gene therapy with MYBPC3. J Mol Cell Cardiol 150:101-108. doi: 10.1016/j.yjmcc.2020.10.003. Epub 2020 Oct 11.PMID: 33049255 Review.

    6. Singh SR, Meyer-Jens M, Alizoti E, Bacon WC, Davis G, Osinska H, Gulick J, Reischmann-Düsener S, Orthey E, McLendon P, Molkentin JD, Schlossarek S, Robbins J, Carrier L (2020) A high throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway. Autophagy Dec 27. doi:10.1080/15548627.2020.1856493. Online ahead of print.

    7. Bezzerides VJ, Prondzynski M,Carrier L, Pu WT (2020) Gene therapy for inherited arrhythmias. Cardiovasc Res 116(9):1635-1650. doi: 10.1093/cvr/cvaa107.PMID: 32321160. Review.

    8. Chen CY, Salomon AK, Caporizzo MA, Curry S, Kelly NA, Bedi K, Bogush AI, Krämer E, Schlossarek S, Janiak P, Carrier L, Margulies KB, Prosser BL (2020) Depletion of vasohibin 1 speeds relaxation in failing human cardiomyocytes. Circ Res 127:e14-e27. doi: 10.1161/CIRCRESAHA.119.315947. Epub 2020 Apr 10.PMID: 32272864.

    9. Singh SR, Kadioglu H, Patel K, Carrier L, Agnetti G (2020) Is Desmin Propensity to Aggregate Part of its Protective Function? Cells 9(2):491. doi: 10.3390/cells9020491.PMID: 32093415 Free PMC article. Review.

    10. Dutsch A, Wijnker PJM, Schlossarek S, Friedrich FW, Krämer E, Braren I, Hirt MN, Letuffe-Brenière D, Rhoden A, Mannhardt I, Eschenhagen T, Carrier L*, Mearini G* (2019) Phosphomimetic cardiac myosin-binding protein C partially rescues cardiomyopathy phenotype in murine engineered heart tissue. Sci Rep Dec;9:18152 *contributed equally.

    11. Prondzynski M*, Lemoine MD*, Zech ATL, Horváth A, Di Mauro V, Koivumäki JT, Kresin N, Busch J, Krause T, Krämer E, Schlossarek S, Spohn M, Friedrich FW, Münch J, Laufer SD, Redwood C, Volk AE, Hansen A, Mearini G, Catalucci D, Meyer C, Christ T, Patten M, Eschenhagen T, Carrier L (2019) Disease modeling of a mutation in a-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy. EMBO Mol Med Nov 3. DOI:10.15252/emmm.201911115.

    12. Zech ATL, Singh SR, Schlossarek S, Carrier L (2019) Autophagy in cardiomyopathies. Biochim Biophys Acta Mol Cell Res 1867(3):118432. doi: 10.1016/j.bbamcr.2019.01.013 PMID: 30831130. Review.

    13. Eschenhagen T, Carrier L (2019) Cardiomyopathy phenotypes in human-induced pluripotent stem cell-derived cardiomyocytes-a systematic review. Pflugers Arch 471(5):755-768. doi: 10.1007/s00424-018-2214-0. PMID: 30324321.

    14. Prondzynski M, Mearini G, Carrier L (2019) Gene therapy strategies in the treatment of hypertrophic cardiomyopathy. Pflugers Arch 471(5):807-815. doi: 10.1007/s00424-018-2173-5. PMID: 29971600 Review. 15. Mosqueira D, Mannhardt I, Bhagwan J, Lis-Stimak K, Prondzynski M, Smith JGW, Carrier L, Gaffney D, Eschenhagen T, Hansen A, Denning C (2018) CRISPR/Cas9 editing in hPSC-cardiomyocytes highlights arrhythmias, hypo-contractility and energy depletion as potential therapeutic targets for HCM. Eur Heart J 14;39-3879-3892. doi: 10.1093/eurheartj/ehy249. PMID: 29741611

    16. Braumann S, Thottakara T, Stücker S, Düsener-Reischman S, Krämer E, Gross J, Hirt M, Doroudgar S, Carrier L, Friedrich FW (2018) S100A4 as a target of the E3-ligase Asb2β and its effect on engineered heart tissue. Front Physiol 9:1292. doi: 10.3389/fphys.2018.01292

    17. Singh SR, Zech ATL, Geertz B, Reischmann-Düsener S, Osinska H, Prondzynski M, Krämer E, Meng Q, Redwood C, van der Velden J, Robbins J, Schlossarek S, Carrier L (2017) Activation of autophagy ameliorates cardiomyopathy in Mybpc3-targeted knock-in mice. Circ-Heart Fail, Oct;10(10). doi: 10.1161/CIRCHEARTFAILURE.117.004140.

    18. Prondzynski M, Krämer E, Laufer SD, Shibamiya A, Pless O, Müller OJ, Münch J, Redwood C, Hansen A, Patten M, Eschenhagen T, Mearini G, Carrier L (2017) Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-derived cardiomyocytes. Mol Ther Nucl Acids 7: 475-486. doi: 10.1016/j.omtn.2017.05.008.

    19. Flenner F, Friedrich FW, Ungeheuer N, Christ T, Geertz B, Reischmann S, Wagner S, Stathopoulou K, Söhren K, Weinberger F, Schwedhelm E, Cuello F, Maier L, Eschenhagen T, Carrier L (2016) Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effects in vivo in a mouse model of hypertrophic cardiomyopathy. Cardiovasc Res 109:90-102. doi: 10.1093/cvr/cvv247.

    20. Wijnker PJM, Friedrich FW, Dutsch A, Eder A, Vollert I, Mearini G, Eschenhagen T, van der Velden J, Carrier L (2016) Comparison of the effects of a truncating and a missense MYBPC3 mutations on contractile parameters of engineered heart tissue. J Mol Cell Cardiol 97:82-92. doi: 10.1016/j.yjmcc.2016.03.003.

    21. Friedrich FW, Flenner F, Nasib M, Eschenhagen T, Carrier L (2016) Epigallocatechin-3-gallate accelerates relaxation and Ca2+ transient decay and desensitizes myofilaments in healthy and Mybpc3-targeted knock-in cardiomyopathic mice. Front Physiol eCollection 2016. doi: 10.3389/fphys.2016.00607.

  • Recent Funding (2016-2021):

    2021-2025: Cytoskeleton regulation in cardiomyocyte homeostasis in health and disease – Leducq Foundation – EUR 5.655,000 (EUR 860,006 to Carrier, European coordinator).

    2021-2025: Modelling pathomechanisms of cardiomyopathy in induced pluripotent stem cell-derived cardiac cells – German Centre for Cardiovascular Research (DZHK) – EUR 2.718,529 (EUR 573,059 to Carrier, co-PI with A. Hansen and F. Cuello).

    2021: The role of Janus kinase 1 in cardiac proteotoxicity – German Centre for Cardiovascular Research (DZHK) – Promotion of Women Sientists – EUR 76,494 to Singh, PI.

    2020-2022: Evaluation of ZNF418 overexpression in mice as a therapy for hypertrophic cardiomyopathy – Deutsche Stiftung für Herzforschung – EUR 59,840 to Singh, PI. 2019-2020 Hypertrophic cardiomyopathy – from gene identification to individualized therapy – German Centre for Cardiovascular Research (DZHK) – EUR 225,735 to Carrier, PI.

    2018-2019: Evaluating the autophagic flux in human iPSC-derived cardiomyocytes with hypertrophic cardiomyopathy phenotype, German Heart Research Foundation EUR 56,000 to Schlossarek, PI.

    2015-2018: iPSC-mediated disease modeling in engineered heart tissue: molecular correction, including CRISPR/Cas9 technology, German Centre for Cardiovascular Research (DZHK) EUR 440,280 to Carrier, PI.

    2011-2017: Proteotoxicity: an unappreciated mechanism of heart disease and its potential for novel therapeutics, Leducq Foundation EUR 680,000 to Carrier, PI.

  • Patent:

    Gene Therapy Vectors for Treating Cardiomyopathies, granted European PCT Nr. EP2014057984, granted US 14/758188, Canadian Patent application 2,944,186.

Research Team

Zurück zur Übersicht