Funded by: Alexander von Humboldt Foundation

Duration: 01.01.2014 - 31.10.2017

The project is based on an Institutspartnerschaft founded by the Alexander von Humboldt Foundation between the Klipp, Herrmann and Del Rio groups in Germany and Mexico.

The project aims to develop selective delivery peptides, so-called hunter-killer peptides. It is based on the interest of three groups of research, one in Mexico (Gabriel Del Rio at the National University of Mexico, UNAM) and two in Germany (Edda Klipp and Andreas Herrmann at the Humboldt-Universität zu Berlin), to collaborate in the study of this class of peptides with a long-term perspective.

Hunter-killer peptides were designed to kill targeted cells as a novel class of molecules useful in treating different diseases. The idea is based on combining two peptides: a ligand peptide (hunter) and a Cationic Antibacterial Peptide (killer); depending on the context we will refer to killer peptides as CAPs. The proposed mechanism of action for these peptides implies that the hunter peptide would bind to its receptor on target cells and internalize the killer peptide by receptor-mediated endocytosis; the killer peptide would in turn affect mitochondrial membrane of the target cell to ultimately kill the targeted cells by apoptosis. The hunter and the killer peptide are linked through a linker peptide (Gly-Gly dipeptide). While hunter-killer peptides have been shown to be effective in treating cancer and obesity in animal models, they present toxicity and sometimes the fusion of the hunter to the killer peptide inactivates any of the two activities. Furthermore, the cost of synthesis of some of these peptides is expensive both because of the size (larger than 20 residues) and the presence of disulfide bonds.

In an attempt to prevent the inactivation of the hunter and/or killer activities when these are combined in a single polypeptide and to reduce the cost of synthesis, we designed Iztli peptides. These peptides embed the hunter peptide within the sequence of a killer peptide, thus both activities are merged into a single functional domain. For proof of principle, Iztli peptides were designed against Saccharomyces cerevisiae, by using the alpha-pheromone as the hunter. This yeast is a good model to study the molecular and genetic events that take place in a eukaryotic cells in the presence of hunter-killer peptides: yeast cells have mitochondria that can be targeted by the killer peptide and present apoptosis-like phenomena. Iztli peptides specifically target the mating type A (MatA) cells that express the alpha-pheromone’s receptor, Ste2p. To create a cationic antibacterial peptide (CAP; this is also referred to as the killer peptide) that embeds the alpha-pheromone, every possible amino acid residue but Cysteine was added on either or both N- and C-terminus to identify peptide sequences with the physicochemical properties of CAPs. We have shown that Iztli peptides selectively kill MatA cells and present antibacterial and pheromone activities. The peptides were named after an Aztec’s god, which was represented as a small dagger used specifically to kill.

Thus, Iztli peptides represent a novel class of molecules useful to internalize cargoes (hunter-peptides) inside targeted cells. The use of S. cerevisiae as targeting cells will facilitate the study of the mechanism of action of these peptides. We propose that the design of Iztli peptides may be used to improve on peptides currently used to deliver cargoes inside cells referred to as Cell Penetrating Peptides (CPPs).

In an ongoing project we are trying to understand how the yeast, S. cerevisiae, progression in the cell cycle is influenced by the metabolic oscillations that arrise from the cell‘s temporal and spatial administration of the carbon source obtained as nutrient. Both metabolism and the cell division cycle are oscillating processes that are coupled in the cell. The coupling of oscillators can be represented in a mathematical model that must be fitted to experimental data in order to represent reality. Two metabolites are being used as a guide to model the metabolic dynamics in single cells: published data on NADH levels and measurments of ATP levels in our own lab through fluoresence microscopy.

People

Paula Martinell Garcia

Funded by: BMBF, e:Bio Cellemental

Duration: 01.05.2012 - 31.10.2017

The complexity of cellular networks is an outstanding challenge for documentation, visualisation and mathematical modeling. In this project, we develop a new way to describe these networks that minimizes the combinatorial complexity and allows an automatic visualisation and export to mathematical models.

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Dr. Marcus Krantz

Dr. Timo Lubitz

Dr. Jesper Romers

Dr. Magdalena Rother

Ulrike Münzner

Sebastian Thieme

Mathias Wajnberg

Funded by: BMBF

Duration: 01.09.2016 - 31.12.2018, extended 31.12.2020

LiSyM (Liver Systems Medicine) represents a research network of German centers and institutions, brought together by a 20 Million Euro funding program of the German Government, in which mathematicians, modelers, pharmacologists, molecular biologists and clinical scientists work together to develop a Systems Medicine approach to study early and advanced liver disease.

The aim of this unique research program is to acquire and use new experimental data and data from existing data bases to build computational models that facilitate decision making at the patient's bedside and to predict the actions of new medicines in the treatment of metabolic liver disease. 

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Dr. Judith Wodke
Dr. Josch Konstantin Pauling

Funded by: Marie Skłodowska-Curie Innovative Training Network

Duration: 01.01.2015 - 31.12.2018

The ProteinFactory partnership builds new-generation platforms for bacterial protein secretion and trains a cohort of young scientists in the field of recombinant protein production.

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Ana Bulović

Funded by: European Union's Horizon 2020 research and innovation programme under grant agreement No 675585, Marie Curie ITN "SyMBioSys"

Duration: 01.09.2015 - 31.08.2019

The main objective of SyMBioSys is to train a new generation of innovative and entrepreneurial early-stage researchers (ESRs). SyMBioSys researchers will develop cutting-edge kinetic models for biological processes via systems engineering research and will exploit these for designing novel biotechnological applications. To achieve this, the ESRs projects will be integrated in such a way that all will collaboratively contribute to the building and usage of proper kinetic models of complex biological systems.

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People

Olufemi Bolaji

Roman Rainer

Funded by: DFG

Duration: 01.07.2016 - 30.06.2020

The photosystem II in Chlamydomonas reinhardtii consists of two core subunits, the D1 and the D2 subunit. The translation of these subunits is controlled via two independent pathways, which are both linked to the metabolic processes within the chloroplast. The translation of D1 is linked to the synthesis of Acetyl-CoA and therefore also to the fatty acid synthesis, while the translation of D2 is controlled by an enzyme which uses NADPH from the Oxidative Pentose Phosphate Pathway.
The two main modulators here are NTRC, which controls the translation of the D2 subunit, and DLA2, which controls the translation of the D1 subunit. To better understand the role and activity of these two proteins, we want to build a kinetic ODE model of the system which governs the translation of subunits of Photosystem II.

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Maria Dost
Stephan Adler

Funded by: DFG

Despite enormous endeavors in antimalarial research the disease remains a major global health issue.
The absence of an effective vaccine and emerging resistance of the parasite against approved anti-malarial drugs provokes the need for new approaches to fight malaria.
The IRTG2290 aims to combine experimental and theoretical approaches to develop new curative drugs against malaria.
Our group thrives to build comprehensive mathematical models of the ion homeostasis and lipid metabolism of the intra-erythrocytic parasite, as both present potential drug targets.
Using ODE and Agent-based approaches we will incorporate data acquired by partners from the IRTG2290.

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People

Jorin Diemer

Maxim Karnetzki