Ruprecht-Karls-Universität Heidelberg
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Kzhyshkowska0119 - Scientist (f/m) / PhD position
Project no:
Kzhyshkowska0119

Project leader:

Project supervisor:
Kzhyshkowska, Julia
Application deadline:
15. Dec 2019
Start of PhD project:
1. Jan 2020

Project description:

Title:
Analysis of macrophage responses to novel implant materials
Summary:
Mechanism of implant failure has recently become aim of intensive research. Since the bone fixation devices and artificial joints comprise 44% of all medical devices, the research is focused on the increase their service life. Implant osseointegration represents the most important cause of loosening in dental implants and artificial joint surgery. Macrophages are key innate immune cells that decide whether implant materials will be accepted or rejected. Intolerance of implant materials is even more pronounced in diabetic patients due to the impaired healing function, and new biomaterials are needed in order to improve the integration of implant in diabetic patients. The main aim of the international collaborative proposal is to generate novel Ti-based implants for long term service and biodegradable Mg alloys for short term with controllable dissolution rate. The goal of the PhD project is to investigate the immunocompatibility and immunomodulation behaviour of the novel implants

The analysis of the Immunocompatibility and immunomodulatory properties of the developed layers will be examined in the ex vivo system based on human primary monocyte-derived macrophages. Our laboratory has made a profound contribution in the identification of novel macrophage functions and macrophage-derived therapeutic targets in major human pathologies. We have also published a proof-of-concept therapeutic programming of human macrophages for the regenerative medicine.

The PhD student will apply next generation sequencing, RT-PCR, immunological techniques and functional secretory, migration and endocytosis assays to identify the effect of layers on the activation of pro-and anti-inflammatory, pro-fibrotic and healing activities of macrophages. The layers with the ability to support healing and suppress inflammation will be identified. This model system enables also the identification of the spectrum of the individual responses to the layer that is the first step towards patient stratification and selection of specific variants of layers for individual patients.

We specific aims of the PhD project are: 1) to identify implant-induced transcriptional profile, 2) secretion profile and 3) phagocytic and endocytic activity of primary human pro-inflammatory and healing macrophages; and 4) to examine how diabetic conditions (hyperglycemia and dyslipidemia) affect responses of macrophages on various types of alloys. As a result, the most immune compatible Ti-based implants for long term service and biodegradable Mg alloys will be selected for the application in diabetic patients.

References:
Yin S, Wang N, Riabov V, Mossel DM, Larionova I, Schledzewski K, Trofimova O, Sevastyanova T, Zajakina A, Schmuttermaier C, Gratchev A, Flatley A, Kremmer E, Zavyalova M, Cherdyntseva N, Simon-Keller K, Marx A, Klüter H, Goerdt S, Kzhyshkowska J. SI-CLP inhibits the growth of mouse mammary adenocarcinoma by preventing recruitment of tumor-associated macrophages. Int J Cancer. 2019 Sep 16. doi: 10.1002/ijc.32685. [Epub ahead of print]

Liu T, Larionova I, Litviakov N, Riabov V, Zavyalova M, Tsyganov M, Buldakov M, Song B, Moganti K, Kazantseva P, Slonimskaya E, Kremmer E, Flatley A, Klüter H, Cherdyntseva N, Kzhyshkowska J. Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy. Oncoimmunology. 2018 Mar 13;7(6):e1436922.

Riabov V, Salazar F, Htwe SS, Gudima A, Schmuttermaier C, Barthes J, Knopf-Marques H, Klüter H, Ghaemmaghami AM, Vrana NE, Kzhyshkowska J. Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation. Acta Biomater. 2017 Apr 15;53:389-398.

Ovsiy I, Riabov V, Manousaridis I, Michel J, Moganti K, Yin S, Liu T, Sticht C, Kremmer E, Harmsen MC, Goerdt S, Gratchev A, Kzhyshkowska J. IL-4 driven transcription factor FoxQ1 is expressed by monocytes in atopic dermatitis and stimulates monocyte migration. Sci Rep. 2017 Dec 4;7(1):16847.
Moganti K, Li F, Schmuttermaier C, Riemann S, Klüter H, Gratchev A, Harmsen MC, Kzhyshkowska J. Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages. Immunobiology. 2017 Oct;222(10):952-959.

Swystun LL, Lai JD, Notley C, Georgescu I, Paine AS, Mewburn J, Nesbitt K, Schledzewski K, Géraud C, Kzhyshkowska J, Goerdt S, Hopman W, Montgomery RR, James PD, Lillicrap D. The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity. J Clin Invest. 2018 Aug 31;128(9):4057-4073

Alidori S, Bowman RL, Yarilin D, Romin Y, Barlas A, Mulvey JJ, Fujisawa S, Xu K, Ruggiero A, Riabov V, Thorek DL, Ulmert HD, Brea EJ, Behling K, Kzhyshkowska J, Manova-Todorova K, Scheinberg DA, McDevitt MR. Deconvoluting hepatic processing of carbon nanotubes. Nat Commun. 2016 Jul 29;7:12343.
Methods that will be used:
1. Human primary macrophages functional system
2. RT-PCR, Next generation sequencing
3. Western blotting
4. ELISA
5. Immunohistology
6. Confocal microscopy
7. Functional cellular assays: migration, phagocytosis, endocytosis

Cooperation partners:
Personal qualifications:
We are looking for highly motivated PhD student interested in the fundamental mechanism of metabolic diseases and translation of laboratory finding into clinic. Master degree in biology, veterinary sciences or pharmacology is preferential. Previous experimental experience in basic molecular biology, protein analytics and/or cell culture techniques are of advantage but not a condition. Team-working abilities are essential. Critical independent thinking is encouraged. The successful candidate will be integrated in the international collaborative network and will strongly benefit from the educational program of the DIAMICOM consortium. The successful candidate will develop excellent experimental, communication and presentation skills and exposed to the industrial R&D environment that gives an advantage for career development in the academia and industry.
Keywords:
regenerative medicine, transcription, signal transduction, inflammation, innate immunity, macrophage