Dear Visitor!

Welcome to the website (under construction) of the graduate school “Resolution of Inflammation” (Auflösung von Entzündungsreaktionen) - AVE founded by the German Research Association (DFG). For your application as PhD please find the following information concerning our research projects. In your application, please name the project(s) you would like to apply for.

Please send your application as single pdf-file to

Application Deadline: July 22nd, 2017

Research profile of the GRK 2336:
AVE - Resolution of Inflammation

Our graduate school (RTG/GRK) aims to train PhD students in the field of resolution of inflammation with a focus on the elucidation of basic mechanisms and their dysregulation in disease. By providing a structured training programme coupled with an ambitious, cutting edge scientific research project we hope to attract young scientists towards this emerging field of science. Our scientific consortium studies fundamental principles of resolution pathways and mechanisms of dysregulated resolution during acute and chronic inflammation. The elucidation of mechanisms involved possesses enormous potential for translational research and subsequent therapeutic development and is an ideal training ground for the next generation of young translational scientists. The educational program of the RTG will provide the necessary theoretical and methodological training to ensure an efficient and successful completion of each PhD thesis. This will be backed up by an individualized supervision and coaching program, as well as topic related seminars, practical courses and soft skill workshops.

In detail, the RTG is comprised of

11 Projects
10 Different Institutes
3 Scientific Clusters

The three scientific clusters are representing the research areas:

  • 1) signals derived from dying cells
  • 2) polarization of immune cells
  • 3) restoration of barrier function

Cluster 1:

Signals derived from dying cells

Cell Death is central during inflammation. Immune cells die after activation by pathogen-derived mediators, while other cells viability in response to exogenous (paracetamol and other drugs) or endogenous noxes (Fas/FasL, hypoxia). There are different types of cell death including apoptosis, necrosis, or necroptosis. It is not understood how the resolution of inflammation is differentially influenced by these types of cell death. Cluster 1 comprises three projects:

Project 1:

Interleukin 38 as a new regulator of the
resolution of inflammation

IL-1 family proteins are critical regulators of inflammation. The new IL-1 family receptor antagonist IL-38, which is released from apoptotic cells, blocks the generation of TH17 cells. The project follows the hypothesis that IL-38 constitutes a novel endogenous mediator of the resolution of inflammation. This hypothesis will be tested using in vitro models of immune cell activation, in vivo inflammation models that allow interrogating resolution, and patient material.

Principle Investigators:

PD Dr. Andreas Weigert
Institute of Biochemistry 1
Goethe-University Frankfurt

www.pathobiochemie1.de

Prof. Dr. Harald Burkhardt
Med. Klinik II, Rheumatology
University Clinic Frankfurt

www.kgu.de/kliniken-institut-zentren

Project 2:

The role of necroptosis versus apoptosis
in the resolution of inflammation

Necroptosis and apoptosis differentially regulate immune responses. This project aims at elucidating the role of necroptosis versus apoptosis in the resolution of inflammation. The effects of necroptotic/apoptotic cells on the release of regulators of the resolution of inflammation and on the phenotype of cocultivated activated macrophages and DCs will be analyzed. In an in vivo model of zymosan-induced peritonitis, necroptotic/apoptotic fibroblasts will be injected i.p. to examine their effects on the resolution of inflammation.

Principle Investigator:

Prof. Dr. Simone Fulda
Institute for Experimental Cancer Research in Pediatrics
University Clinic Frankfurt

www.kinderkrebsstiftung-frankfurt.de

Project 3:

Termination of necroinflammation mediating recovery
from Paracetamol-induced liver injury

Depending on the dose, paracetamol-induced hepatic necroinflammation and injury can either be fatal or reversible with organ regeneration prevailing. Herein, mechanisms that determine successful recovery from liver damage will be investigated in experimental paracetamol-induced hepatic injury. Results obtained may advance current knowledge of paradigmatic paracetamol intoxication and may likewise open the avenue to novel strategies for the treatment of hepatic inflammatory diseases.

Principle Investigator:

Prof. Dr. Heiko Mühl
Institute of General Pharmacology and Toxicology
Goethe-University Frankfurt

www.pzf.de/allg

Cluster 2:

Polarization of immune cells

Phagocytosis of dying cells, cell debris as well as pathogens by macropghages and mast cells, is an important process during resolution of inflammation. The projects within cluster 2 deal with polarization of phagocytes induced by endogenous and exogenous signals and explore signal transduction pathways activated or inhibited during phagocyte-induced resolution of inflammation. Cluster 2 comprises five projects:

Project 4:

5-/15-Lipoxygenase interaction as regulatory principle in the
lipoxin synthesis during resolution of inflammation

The formation of specialized proresolving mediators (SPM) such as lipoxins and resolvins requires the concerted action of 5-lipoxygenase (5-LO) and 12-LO or 15-LO. The regulation of LOs in monocytes and polarized macrophages as well as the biosynthetic pathways involved in SPM formation will be investigated in this project.

Principle Investigator:

Prof. Dieter Steinhilber
Institute of Biochemistry 1
Goethe-University Frankfurt

www.pathobiochemie1.de

Project 5:

Role of cytochrome P450 (CYP) and soluble epoxide
hydrolase (sEH) in macrophage polarization and resolution
of inflammation

Cytochrome P450 (CYP) enzymes generate lipid epoxides from endogenous polyunsaturated fatty acids that are further metabolized by the soluble epoxide hydrolase (sEH). This project will determine the importance of CYP2S1, Cyp2c44 and sEH products in macrophage polarization and in the maintenance versus resolution of inflammation. Use will be made of mice lacking CYP and the sEH in myeloid cells and in vivo models will focus on acute peritonitis and atherosclerosis.

Principle Investigator:

Prof. Ingrid Fleming
Institute for Vascular Signalling
Goethe University Frankfurt

www.vrc.uni-frankfurt.de

Project 6:

mPGES-1 in macrophages during resolution of inflammation

The microsomal prostaglandin E synthase (mPGES-1), together with cyclooxygenase, produces prostaglandin E2 (PGE2). Despite known as a pro-inflammatory agent, PGE2 also adds to macrophage polarization during resolution of inflammation. Molecular mechanisms how PGE2 causes resolution of inflammation remains elusive. Having specific inhibitors available, we block mPGES-1 and follow the behavior of macrophages in vitro and in vivo, determine mRNA profiles (deep-sequencing), and characterize relevant targets by knockdown/knockout vs. overexpression strategies.

Principle Investigators:

Prof. Dr. Bernhard Brüne
Institute of Biochemistry 1
Goethe-University Frankfurt

www.pathobiochemie1.de

PD Dr. Tobias Schmid
Institute of Biochemistry 1
Goethe-University Frankfurt

www.pathobiochemie1.de

Project 7:

Regulation of resolution of inflammation by mast cells

Mast cells are known for their proinflammatory properties i.e. in promoting allergies. However, they have also the power to suppress immune answers and to promote resolution of inflammation. So far signals that switch mast cells from a proinflammatory to an antiinflammatory phenotype are largely unknown. Here, we aim to identify signals that promote antiinflammatory phenotypes in mast cells as well as downstream effector cells mediating the mast cell-dependent resolution of inflammation.

Principle Investigator:

Prof. Dr. Klaus Scholich
Institute of Clinical Pharmacology
Goethe University Frankfurt

www.kgu.de/zpharm/klin

Project 8:

The role of IKKε in the resolution of inflammation
in atherosclerosis

IκB kinase ε (IKKκ) modulates NF-κB signal transduction cascades and inflammatory reactions. In our project, we aim to investigate the role of IKKε in macrophages in the resolution of inflammation, which is disturbed in atherosclerosis. Therefore, we will perform cell culture experiments as well as mouse models of peritonitis and atherosclerosis using wild type, ApoE knockout and ApoE/IKKε double knockout mice with or without IKKε inhibitor, respectively.

Principle Investigator:

Prof. Dr. Ellen Niedernberger
Institute of Clinical Pharmacology
Goethe University Frankfurt

www.kgu.de/zpharm/klin

Cluster 3:

Restoration of barrier function

A key process during inflammation is the loss of epithelial and endothelial barrier function. This enables immune cells to invade the subendothelial space or allows noxious substances to enter the body and trigger immune reactions. Restoration of barrier function is a fundamental principle during the resolution of inflammation. Regeneration of biological barriers requires a crosstalk between cells of the barrier and (anti-inflammatory) immune cells. Underlying signalling pathways are analysed within the three projects of cluster 3:

Project 9:

Pharmacological inhibition of BMP2K to promote
resolution of inflammation

Chronic inflammatory diseases are characterized by constant leukocyte infiltration and ongoing angiogenesis due to an endothelial barrier dysfunction. This project aims to restore the barrier functionality of the endothelium and to promote the resolution of inflammation. BMP2K, an as yet widely uncharacterized kinase, is primarily addressed by the small molecule inhibitor C81. The application of C81 as well as BMP2K knockdown experiments will be used to achieve a successful resolution of inflammation

Principle Investigator:

Prof. Dr. Robert Fürst
Institute of Pharmaceutical Biology
Goethe-University Frankfurt

www.uni-frankfurt.de/53344830/PharmBio

Project 10:

Role of the NADPH Oxidase Nox4 in the termination of
vascular inflammatory reaction after vascular injury

Nox4 is a hydrogen peroxide producing NADPH oxidase. It is upregulated after vascular injury and its loss results in inflammatory activation, vascular dysfunction and accelerated atherosclerosis. Using mouse models and patient samples, the role of Nox4 in restenosis and resolution of inflammation after injury will be determined. Redox-proteomics will be used to identify Nox4-differentially oxidized proteins. These will be subsequently tested to alter the course of inflammation after vascular injury.

Principle Investigator:

Prof. Dr. Ralf P. Brandes
Institute of Cardiovascular Physiology
Goethe-University Frankfurt

www.vrc.uni-frankfurt.de

Project 11:

Functional analysis of Reg3β in the wound healing
of acute colitis

The regenerating (Reg) protein family was discovered independently during acute pancreatitis and pancreatic islet regeneration. The Reg3 subclass family member, Reg3β is up-regulated upon tissue damage or after microbial invasion. Stat3 knockout mice show impaired wound healing during acute colitis. Reg3β is a Stat3 downstream target gene in murine intestinal epithelial cells. It is not known whether the worsened healing of Stat3 knockout mice is due to diminished Reg3β expression.

Principle Investigator:

Prof. Florian Greten
Georg-Speyer-Haus

www.georg-speyer-haus.de