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Carlie de Vries

Nuclear Receptor Nur77 & Co-regulator FHL2

Carlie de Vries Lab

Prof. Carlie JM de Vries, PhD; Chair department


Biosketch

Carlie de Vries was trained as a molecular biologist at the University of Utrecht in The Netherlands after which she worked on her thesis at Sanquin Laboratories (Amsterdam). She did a postdoc at the University of California San Francisco, where she cloned the first VEGF-receptor, followed by a postdoc at the Hubrecht Institute in Utrecht studying Activin A in zebrafish. After this she started her own research group at the department of Medical Biochemistry. Since 2008 De Vries is full professor at the University of Amsterdam, and she is heading the department as of 2014.


The de Vries-lab studies the nuclear receptor Nur77 and its co-regulator FHL2. Nur77 is instrumental in the resolution of the inflammatory response of macrophages and tumor infiltrating T cells. Unravelling the exact working mechanism of the transcription factor Nur77 requires detailed structure-function analyses. This knowledge is crucial to design innovative strategies to modulate the activity of Nur77.

We recently demonstrated that Four and a half LIM-domain 2 (FHL2) is involved in metabolism; it regulates insulin secretion in beta cells of the pancreas and modulates adipose tissue.

c.j.devries-at-amsterdamumc.nl

Carlie de Vries Lab

Prof. Carlie JM de Vries, PhD;

Chair department


Biosketch

Carlie de Vries was trained as a molecular biologist at the University of Utrecht in The Netherlands after which she worked on her thesis at Sanquin Laboratories (Amsterdam). She did a postdoc at the University of California San Francisco, where she cloned the first VEGF-receptor, followed by a postdoc at the Hubrecht Institute in Utrecht studying Activin A in zebrafish. After this she started her own research group at the department of Medical Biochemistry. Since 2008 De Vries is full professor at the University of Amsterdam, and she is heading the department as of 2014.


The de Vries-lab studies the nuclear receptor Nur77 and its co-regulator FHL2. Nur77 is instrumental in the resolution of the inflammatory response of macrophages and tumor infiltrating T cells. Unravelling the exact working mechanism of the transcription factor Nur77 requires detailed structure-function analyses. This knowledge is crucial to design innovative strategies to modulate the activity of Nur77.

We recently demonstrated that Four and a half LIM-domain 2 (FHL2) is involved in metabolism; it regulates insulin secretion in beta cells of the pancreas and modulates adipose tissue.


c.j.devries@amsterdamumc.nl

De Vries Lab

Research

Anti-inflammatory function of Nur77 in Macrophages

The nuclear receptor Nur77 has a crucial function in the resolution phase of macrophage-mediated inflammation. Chronic inflammatory diseases such as atherosclerosis, inflammatory bowel diseases and rheumatoid arthritis are caused by prolonged activation of immune cells such as macrophages. Under normal circumstances, macrophages react to local infections with an initial inflammatory response, involving the secretion of cytokines and chemokines. This inflammatory process needs to stop to avoid tissue damage; this is called the resolution phase of inflammation. 

We have demonstrated that macrophages deficient for Nur77 exhibit prolonged expression of cytokines, which involves a modulation of mitochondrial metabolism.

In our current studies we unravel the function of Nur77 in macrophages by RNA-seq, ChIP-seq and RIME in activated macrophages. 

Koenis et al, Cell Rep

Nur77 protein function - homodimerization and heterodimerization

The nuclear receptor Nur77 is  a transcription factor, and according to current literature it can act as a monomer on a single response element (NBRE), as a homodimer on an everted repeat (ER6), and as a heterodimer with RXR binding direct repeats (DR5). Nur77 is called an 'orphan receptor' because so far, no traditional nuclear receptor ligand has been identified.

In this project we aim to delineate the dimerization interface of Nur77. This knowledge will guide the way to designing small-molecule drugs that modulate Nur77 acitivity in inflammatory diseases. We apply purified Nur77-(variant) proteins, biolayer interferometry (BLI), native protein gel-electrophoresis, NanoBiT-protein-protein interaction, luciferase reporter assays.

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Low FHL2 improves insulin secretion and limits obesity

Four and a Half LIM domain 2 (FHL2) is a key modulator of signal transduction pathways and gene expression. Through its specific interactome it adjusts the activity of other proteins. FHL2-deficient mice clear glucose faster due to a faster insulin release. We demonstrated that beta-cells express more GLUT2 and have lower ROS levels.

In response to a high-fat diet, FHL2-KO mice gain less weight then wild-type littermates. It appears that the white adipose tissue expresses more 'browning' markers upon FHL2 deficiency.

In humans, the FHL2 gene becomes increasingly methylated with age resulting in enhanced FHL2 expression. In line with our mice data, humans with obesity express more FHL2 and less browning genes in white adipose tissue.

Recently, we initiated studies to unravel the role of FHL2 in the blood-brain-barrier and in multiple sclerosis, in collaboration with Prof. dr Elga de Vries (Amsterdam UMC, location VUmc).

Habibe / Clemente et al; Diabetes

Internships

We provide internships for Biomedical and Medical students for at least 5 months.

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De Vries Lab

The team

Carlie de Vries

Carlie de Vries

Principal Investigator

Menno De Winther

Claudia van Tiel

Senior scientist

Inge van der Made

Research technician

Carlie de Vries

Hannah van der Stok

PhD candidate

Alumni

Jayron Habibe

Maria del Pilar Clemente Olivo

Mariska Vos

Duco Koenis

Min Khang Tran

Thijs Pols

Pieter van Loenen

Konda Babu Kurakula

Matthijs Ruiter

Iker Otermin

Anouk Hamers

Anita Klous

Farid Meggouh

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Maarten Janmaat

Jasper Heerkens

Bianca Groenendijk

Peter Bonta

Germaine Benus

Simone van de Graaf

Astrid Mocking

Maaike van Bragt

Jolanda Neele

Marten Engelse

Karin Arkenbout

Marten Engelse

Tanja van Achterberg


Kristina Kovac

Sanne Lith

Carlie de Vries

Publications

FHL2 Genetic Polymorphisms and Pro-Diabetogenic Lipid Profile in the Multiethnic HELIUS Cohort.

Habibe JJ, Boulund U, Clemente-Olivo MP, de Vries CJM, Eringa EC, Nieuwdorp M, Ferwerda B, Zwinderman K, van den Born BH, Galenkamp H, van Raalte DH.Int J Mol Sci. 2023 Feb 22;24(5):4332. doi: 10.3390/ijms24054332.PMID: 36901761 Free PMC article.


Early adipogenesis is repressed through the newly identified FHL2-NFAT5 signaling complex.

Clemente-Olivo MP, Hernández-Quiles M, Sparrius R, van der Stoel MM, Janssen V, Habibe JJ, van den Burg J, Jongejan A, Alcaraz-Sobrevals P, van Es R, Vos H, Kalkhoven E, de Vries CJM.Cell Signal. 2023 Apr;104:110587. doi: 10.1016/j.cellsig.2023.110587. Epub 2023 Jan 5.PMID: 36610523 Free article.


No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice.

Hibender S, Li S, Postma AV, Hoogeland ME, Klaver D, Pouw RB, Niessen HW, Driessen AH, Koolbergen DR, de Vries CJ, Baars MJ, Houweling AC, Krijnen PA, de Waard V.Vasc Biol. 2022 Oct 1;4(1):40-9. doi: 10.1530/VB-22-0016. Online ahead of print.PMID: 36279189 Free PMC article.


Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes.

Habibe JJ, Clemente-Olivo MP, Scheithauer TPM, Rampanelli E, Herrema H, Vos M, Mieremet A, Nieuwdorp M, van Raalte DH, Eringa EC, de Vries CJM.Diabetologia. 2022 Oct;65(10):1721-1733. doi: 10.1007/s00125-022-05750-1. Epub 2022 Jul 8.PMID: 35802167 Free PMC article.


How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease.

Habibe JJ, Clemente-Olivo MP, de Vries CJ.Cells. 2021 Oct 1;10(10):2611. doi: 10.3390/cells10102611.PMID: 34685595 Free PMC article. Review.

 

Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Krüppel-Like Factor 4).

Yap C, Mieremet A, de Vries CJM, Micha D, de Waard V.Arterioscler Thromb Vasc Biol. 2021 Nov;41(11):2693-2707. doi: 10.1161/ATVBAHA.121.316600. Epub 2021 Sep 2.PMID: 34470477 Free PMC article. Review.


Nuclear receptor Nur77: its role in chronic inflammatory diseases.

Lith SC, de Vries CJM.Essays Biochem. 2021 Dec 17;65(6):927-939. doi: 10.1042/EBC20210004.PMID: 34328179 Review.


Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity.

Clemente-Olivo MP, Habibe JJ, Vos M, Ottenhoff R, Jongejan A, Herrema H, Zelcer N, Kooijman S, Rensen PCN, van Raalte DH, Nieuwdorp M, Eringa EC, de Vries CJ.Metabolism. 2021 Aug;121:154815. doi: 10.1016/j.metabol.2021.154815. Epub 2021 Jun 11.PMID: 34119536 Free article.

 

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.

Medzikovic L, Heese H, van Loenen PB, van Roomen CPAA, Hooijkaas IB, Christoffels VM, Creemers EE, de Vries CJM, de Waard V.Int J Mol Sci. 2021 Feb 5;22(4):1600. doi: 10.3390/ijms22041600.PMID: 33562500 Free PMC article.


'Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity.

Lith SC, van Os BW, Seijkens TTP, de Vries CJM.Eur J Immunol. 2020 Nov;50(11):1643-1652. doi: 10.1002/eji.202048869. Epub 2020 Oct 25.PMID: 33063848 Free PMC article. 
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