Ruprecht-Karls-Universität Heidelberg
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Kzhyshkowska0118 - Scientist (f/m) / PhD position
Project no:
Kzhyshkowska0118

Project leader:

Project supervisor:
Kzhyshkowska, Julia
Application deadline:
30. Nov 2018
Start of PhD project:
1. Jan 2019

Project description:

Title:
Mechanism of hyperglycemic control of histone code in metabolic inflammation and microvascular complications
Summary:
Diabetes mellitus is a major public health problem worldwide which seriously impairs the quality of life of the patients. The Global Diabetes Report released by World Health Organization states that the number of diabetics has increased from 108 million in 1980 to 422 million in 2014. Chronic untreated diabetes causes various vascular complications, such as cardiovascular disease, kidney disease, blindness, neural damage while poor perfusion of extremities often requires their amputation. Monocytes and macrophages are key innate immune cells that control inflammatory reactions leading to vascular complications. Histone code is an essential mechanism of epigenetic memory induced by diabetic conditions. Pharmacological targeting of epigenetic networks to reduce cardiovascular disease was suggested. However, the gap of knowledge is the role of the histone code in the pathological macrophage/endothelial cells interactions in hyperglycemic conditions resulting in vascular diabetic complications.

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. During the first and second period of the DIAMICOM project we have developed a unique human ex vivo system to investigate the effect of hyperglycemia on primary macrophages. We demonstrated that hyperglycemia has a direct effect on the specific histone modifications in promoters of pro-inflammatory genes in human primary macrophages. Using Affymetrix gene expression analysis, we showed hyperglycemia-induced differential expression of chemokines/cytokines, chemokine receptors, and S100 calcium binding protein family. We have established chromatin immunoprecipitation (ChIP) in primary human macrophages, and demonstrated that hyperglycemia activates the specific histone code on the promoters of the pro-inflammatory genes.

The aims of the PhD project are: 1) to identify histone-modifying enzymes responsible for the hyperglycemia-induced epigenetic changes in macrophages; 2) to identify the mechanisms of activation of histone-modifying enzymes by signal transduction pathways and mitochondrial stress; 3) to identify the reversibility of hyperglycemic memory fixed in the histone code in macrophages, 4) to identify the effect of the blockade of histone modifying enzymes on the macrophages/endothelial functional interactions.

The results of the project will elucidate how targeting of the epigenetic mechanisms can abrogate pathological monocytes/endothelial cell cross-talk and prevent/reduce microvascular complications

References:
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.

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.

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

Hajmousa G, Przybyt E, Pfister F, Paredes-Juarez GA, Moganti K, Busch S, Kuipers J, Klaassen I, van Luyn MJA, Krenning G, Hammes HP, Harmsen MC. Human adipose tissue-derived stromal cells act as functional pericytes in mice and suppress high-glucose-induced proinflammatory activation of bovine retinal endothelial cells. Diabetologia. 2018 Nov;61(11):2371-2385.

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.

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.

Orekhov AN, Sobenin IA, Gavrilin MA, Gratchev A, Kotyashova SY, Nikiforov NG, Kzhyshkowska J. Macrophages in immunopathology of atherosclerosis: a target for diagnostics and therapy. Curr Pharm Des. 2015;21(9):1172-9.
Methods that will be used:
1. Broad spectrum of molecular biology, epigenetic, protein-protein interaction, immunological and advanced imaging techniques, including chromatic immunoprecipitation, next generation sequencing, RT-PCR, flow cytometry, confocal microscopy.

2. Functional analysis of primary human macrophages and endothelial cells.

3. Analysis of monocytes from patients with diabetes and complications.

4. Mouse models for diabetic complication will be offered by DIAMICON consortium.
Cooperation partners:
Prof. Dr. Peter Nawroth and Dr. Thomas Fleming, University of Heidelberg,
Prof. Dr. Martin C. Harmsen and Dr. Marianne Rots, University Medical Centre Groningen.
DIAMICOM consortium
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 biochemistry, molecular biology or pharmacology is preferential. Previous experimental experience in basic molecular biology, protein analytics and/or cell culture techniques are of advantage. 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 will be familiarized with the industrial R&D environment that gives an advantage for career development in the academia and industry.
Keywords:
diabetes, epigenetic, histone code, signal transduction, inflammation, innate immunity, endothelial cell, macrophage