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Mashreghi lab

With oligonucleotides against "diseased" cells

Introduction
Members
Cooperation partners
Selected Publications

Therapeutic Gene Regulation

Chronic inflammation is not only a key feature of autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, but is currently discussed to be a trigger for the initiation and propagation of osteoarthritis (OA), formerly considered as a non-inflammatory arthritis. Many immune cell types contribute to the persistence of chronic inflammation, either by promoting proinflammatory responses or by interfering with biological processes that allow the regeneration of destroyed tissues. In order to skew the balance in favor of regeneration as opposed to immunopathology, we want to acquire a profound knowledge of the molecular mechanisms that mediate such biological responses.

Our aim is to identify genes and regulatory RNAs and their underlying functions by which they control the activity and survival of cells that contribute to chronic inflammation or help to regenerate destroyed tissues.

For the global identification of such genes and regulatory RNAs, we have established a next generation sequencing platform. This technology allows us to obtain the expression patterns of mRNA and regulatory RNAs even from rare cells or from limited sample material that we obtain from patients with rheumatic diseases as well as OA. Furthermore, we want to interfere with the cellular functions by using therapeutic oligonucleotides targeting the identified mRNA and regulatory RNAs in preclinical models of inflammation and osteoarthritis.

So far, we have identified the microRNA, miR-148a, which is upregulated in memory T helper (Th) cells isolated from inflamed tissues of patients with rheumatic joint diseases. We could show that miR-148a directly promotes the survival of repeatedly activated Th1 cells. By using a class of cholesterol-tagged inhibitory oligonucleotides against microRNAs, so called antagomirs, we achieved a significant knock-down of miR-148a in repeatedly activated Th1 cells. This knockdown in turn resulted in an upregulation of the mRNA coding for the proapoptotic protein Bim, which is a target of miR-148a. The consequence of Bim upregulation was enhanced apoptosis of repeatedly activated Th1 cells. Thus, miR-148a qualifies as a therapeutic target in order to deplete proinflammatory Th1 cells by systemic application of antagomirs in chronic inflammatory diseases.

Our results demonstrate that therapeutic oligonucleotides are a suitable tool to reduce the expression of cell intrinsic target RNAs driving chronic inflammation and thus, to selectively modulate or ablate pathogenic cells. In the future we are going to further investigate the potential of therapeutic oligonucleotides including siRNAs and antagomirs in targeting relevant genes and regulatory RNAs that are important in maintaining chronic inflammation and help to achieve remission in degenerative diseases such as OA.

Group Leader
    Dr. Mir-Farzin Mashreghi

Dr. Mir-Farzin Mashreghi

Deutsches Rheuma-Forschungszentrum Berlin
Therapeutic Gene Regulation
Charitéplatz 1
10117 Berlin

Tel. +49 (0)30 28460-752
Fax +49 (0)30 28460-603
mashreghi@drfz.de

Keywords
Regulatory RNA
Oligonucleotide therapy
Gene regulation
Next Generation Sequencing
Chronic diseases

Das Projekt "Entwicklung therapeutischer Oligonukleotide" wird von EFRE gefördert.
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Group leader
Dr. rer. nat. Mir-Farzin Mashreghi

Scientists
Dr. rer. nat. Gitta Anne Heinz
Dr. rer nat. Patrick Maschmeyer
Dr. rer. nat. Frederik Heinrich

PhD students
Markus Bardua
Cam Loan Tran

Bachelor/Diploma/Master students
Vanessa Treffner
Sarah Schimmelpfennig
Melanie Klingauf

Group Leader
    Dr. Mir-Farzin Mashreghi

Dr. Mir-Farzin Mashreghi

Deutsches Rheuma-Forschungszentrum Berlin
Therapeutic Gene Regulation
Charitéplatz 1
10117 Berlin

Tel. +49 (0)30 28460-752
Fax +49 (0)30 28460-603
mashreghi@drfz.de

Keywords
Regulatory RNA
Oligonucleotide therapy
Gene regulation
Next Generation Sequencing
Chronic diseases

Das Projekt "Entwicklung therapeutischer Oligonukleotide" wird von EFRE gefördert.
Continue to Cooperation partners

Dr. Tobias Alexander, Klinik für Rheumatologie und klinische Immunologie, Charité-Universitätsmedizin Berlin

Prof. Dr. Klemens Budde, Department of Nephrology, Charité-Universitätsmedizin Berlin

Prof. Dr. Falk Hiepe, Klinik für Rheumatologie und klinische Immunologie, Charité-Universitätsmedizin Berlin

Prof. Dr. Hans-Martin Jäck, Molekulare Immunologie, Universitätsklinikum Erlangen

Dr. Anja Kühl, Institut für Pathologie, Charité-Universitätsmedizin Berlin

Prof. Dr. Michael Lohoff, Institut für Medizinische Mikrobiologie, Philipps University Marburg

Dr. Mareen Matz, Department of Nephrology, Charité-Universitätsmedizin Berlin

Prof. Dr. Nikolaus Rajewsky, Max-Delbrück-Centrum für Molekulare Medizin und Berlin Institute for Medical Systems Biology, Berlin

Prof. Dr. Kai Wucherpfennig, Dana-Farber Cancer Institute, Boston, MA, USA

Group Leader
    Dr. Mir-Farzin Mashreghi

Dr. Mir-Farzin Mashreghi

Deutsches Rheuma-Forschungszentrum Berlin
Therapeutic Gene Regulation
Charitéplatz 1
10117 Berlin

Tel. +49 (0)30 28460-752
Fax +49 (0)30 28460-603
mashreghi@drfz.de

Keywords
Regulatory RNA
Oligonucleotide therapy
Gene regulation
Next Generation Sequencing
Chronic diseases

Das Projekt "Entwicklung therapeutischer Oligonukleotide" wird von EFRE gefördert.
Continue to Selected Publications

1: Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun. 2018 May;89:41-52. doi: 10.1016/j.jaut.2017.11.005. Epub 2017 Dec. PubMed PMID: 29183643; PubMed Central PMCID: PMC5916452.

2: Haftmann C, Stittrich AB, Zimmermann J, Fang Z, Hradilkova K, Bardua M, Westendorf K, Heinz GA, Riedel R, Siede J, Lehmann K, Weinberger EE, Zimmel D, Lauer U, Häupl T, Sieper J, Backhaus M, Neumann C, Hoffmann U, Porstner M, Chen W, Grün JR, Baumgrass R, Matz M, Löhning M, Scheffold A, Wittmann J, Chang HD, Rajewsky N, Jäck HM, Radbruch A, Mashreghi MF. miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim. Eur J Immunol. 2015 Apr;45(4):1192-205. doi: 10.1002/eji.201444633. Epub 2015 Jan 22. PubMed PMID: 25486906; PubMed Central PMCID: PMC4406154.

3: Haftmann C, Riedel R, Porstner M, Wittmann J, Chang HD, Radbruch A, Mashreghi MF. Direct uptake of Antagomirs and efficient knockdown of miRNA in primary B and T lymphocytes. J Immunol Methods. 2015 Nov;426:128-33. doi: 10.1016/j.jim.2015.07.006. Epub 2015 Jul 15. PubMed PMID: 26187895; PubMed Central PMCID: PMC4655414.

4: Stittrich AB, Haftmann C, Sgouroudis E, Kühl AA, Hegazy AN, Panse I, Riedel R, Flossdorf M, Dong J, Fuhrmann F, Heinz GA, Fang Z, Li N, Bissels U, Hatam F, Jahn A, Hammoud B, Matz M, Schulze FM, Baumgrass R, Bosio A, Mollenkopf HJ, Grün J, Thiel A, Chen W, Höfer T, Loddenkemper C, Löhning M, Chang HD, Rajewsky N, Radbruch A, Mashreghi MF. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol. 2010 Nov;11(11):1057-62. doi: 10.1038/ni.1945. Epub 2010 Oct 10. PubMed PMID:20935646.

5: Matz M, Fabritius K, Lorkowski C, Dürr M, Gaedeke J, Durek P, Grün JR, Goestemeyer A, Bachmann F, Wu K, Rudolph B, Schmidt D, Weber U, Haftmann C, Unterwalder N, Lachmann N, Radbruch A, Neumayer HH, Mashreghi MF*, Budde K.* Identification of T Cell-Mediated Vascular Rejection After Kidney Transplantation by the Combined Measurement of 5 Specific MicroRNAs in Blood. Transplantation. 2016 Apr;100(4):898-907. doi: 10.1097/TP.0000000000000873. PubMed PMID: 26444957.*equal contribution

6: Matz M, Lorkowski C, Fabritius K, Durek P, Wu K, Rudolph B, Neumayer HH, Mashreghi MF*, Budde K*. Free microRNA levels in plasma distinguish T-cell mediated rejection from stable graft function after kidney transplantation. Transpl Immunol. 2016 Nov;39:52-59. doi: 10.1016/j.trim.2016.09.001. Epub 2016 Sep 20. PubMed PMID: 27663089. *equal contribution

7: Westendorf K, Durek P, Ayew S, Mashreghi MF, Radbruch A. Chromosomal localisation of the CD4cre transgene in B6·Cg-Tg(Cd4-cre)1Cwi mice. J Immunol Methods. 2016 Sep;436:54-7. doi: 10.1016/j.jim.2016.06.005. Epub 2016 Jun 23. PubMed PMID: 27345256.

8: Bothur E, Raifer H, Haftmann C, Stittrich AB, Brüstle A, Brenner D, Bollig N, Bieringer M, Kang CH, Reinhard K, Camara B, Huber M, Visekruna A, Steinhoff U, Repenning A, Bauer UM, Sexl V, Radbruch A, Sparwasser T, Mashreghi MF, Wah Mak T, Lohoff M. Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1. Nat Commun. 2015 Oct 13;6:8576. doi: 10.1038/ncomms9576. PubMed PMID: 26815406; PubMed Central PMCID: PMC4633965.

9: Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, Vu Van D, Mages HW, Haftmann C, Riedel R, Grün JR, Schuh W, Kroczek RA, Radbruch A, Mashreghi MF, Hutloff A. ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. J Exp Med. 2015 Feb 9;212(2):217-33. doi: 10.1084/jem.20141432. Epub 2015 Feb 2. PubMed PMID: 25646266; PubMed Central PMCID: PMC4322049.

10: Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018 May;19(5):453-463. doi: 10.1038/s41590-018-0082-6. Epub 2018 Apr 9. PMID: 29632329:

11: Kawano Y, Petkau G, Stehle C, Durek P, Heinz GA, Tanimoto K, Karasuyama H, Mashreghi MF, Romagnani C, Melchers F. Stable lines and clones of long-term proliferating normal, genetically unmodified murine common lymphoid progenitors. Blood. 2018 May 3;131(18):2026-2035. doi: 10.1182/blood-2017-09-805259. Epub 2018 Mar 23. PMID: 29572379

12: Siracusa F, McGrath MA, Maschmeyer P, Bardua M, Lehmann K, Heinz G, Durek P, Heinrich FF, Mashreghi MF, Chang HD, Tokoyoda K, Radbruch A. Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1334-1339. doi: 10.1073/pnas.1715618115. Epub 2018 Jan 22. PMID: 29358404

Group Leader
    Dr. Mir-Farzin Mashreghi

Dr. Mir-Farzin Mashreghi

Deutsches Rheuma-Forschungszentrum Berlin
Therapeutic Gene Regulation
Charitéplatz 1
10117 Berlin

Tel. +49 (0)30 28460-752
Fax +49 (0)30 28460-603
mashreghi@drfz.de

Keywords
Regulatory RNA
Oligonucleotide therapy
Gene regulation
Next Generation Sequencing
Chronic diseases

Das Projekt "Entwicklung therapeutischer Oligonukleotide" wird von EFRE gefördert.
Continue to Introduction