December 11, 2014

FMI scientists secure funding for two projects

Two out of nine newly funded projects in the category Medical Research and Development will come to the Friedrich Miescher Institute for Biomedical Research. Patrick Matthias will lead the VirX project, which aims to elucidate the role of the HDAC6/Ub/aggresome pathway and ubiquitin proteasome system in viral disease. Mohamed Bentires-Alj and Michael Stadler are part of the interdisciplinary consortium studying tumor heterogeneity during progression to metastases in breast cancer.

VirX: A systems approach to the HDAC6/Ub/aggresome pathway and ubiquitin proteasome system in viral disease

The unexpected recent discovery that the cytoplasmic enzyme HDAC6 is a cofactor for influenza virus infection forms the basis of the VirX project led by Patrick Matthias at the FMI. In October 2014, Matthias' lab, together with colleagues from the ETH Zurich, reported in Science that the influenza virus exploits the cellular process that deals with misfolded proteins to crack open its capsid. The viral capsid was shown to mimic misfolded protein aggregates by carrying unanchored ubiquitin. This form of ubiquitin is recognized with high affinity by HDAC6, which is thus recruited to the envelope encasing the viral genome. HDAC6 also binds to the cytoplasmic motor proteins dynein and myosin, forming a complex with HDAC6 at its center. The motor proteins promote movement along microtubules and actin filaments, generating mechanical stress that pulls the viral capsid apart. More information

Together with Urs Greber and Yohei Yamauchi at the University of Zurich, Jörg Stelling at the ETH Zurich, Laurent Kaiser at the University of Geneva, and Heinz Gut at the FMI, Patrick Matthias’ group will take a systems biology approach to further dissect this process. Unlike many systems biology projects, VirX will take a bottom-up approach, starting from molecular and structural biology and going all the way to clinical specimens from infected individuals. The scientists aim to define the core module of the HDAC6-dependent mechanism of uncapping that is necessary for viral infection. They will determine its impact on viral infectivity and seek to design interfering molecules, hoping to develop novel antiviral agents. Mathematical modeling of the role of the core module and its components will be done at the molecular, cellular and organismal level, allowing a systemic description of this novel pathway.

Breast Cancer MetastasiX: Mathematical modeling of tumor heterogeneity during progression to metastases and clinical validation

The project Breast Cancer MetastasiX is a collaborative, interdisciplinary effort involving five principal investigators from academia – including both biologists and clinicians – and three from industry. The participants from academic labs are Mohamed Bentires-Alj (FMI Group leader), Michael Stadler (Head of FMI Computational Biology), Gerhard Christofori (Basel University Professor), Bernd Bodenmiller (Zurich University Professor) and Walter Paul Weber (Head of Basel University Hospital Breast Center and Staff Breast Surgeon), while the industrial participants are M. Rodrίguez Martίnez (IBM Zurich Research Laboratory) and Francesco Hofmann and Tewis Bouwmeester (Novartis Institutes for BioMedical Research in Basel).

Each year, 1.4 million cases of breast cancer occur worldwide and 450,000 women die from this disease, mostly as a result of metastases. The consortium aims to understand the quantitative behavior of breast cancer growth and progression to metastases. The scientists’ main goal is to use a systems biology approach to unravel, integrate and mathematically model the cellular and molecular determinants of breast cancer metastasis. Pathophysiologically relevant models of metastatic breast cancer will be used, and findings will be validated using clinical specimens and patient outcome data.

The projects will run for three years. This was the first and only call for MRD projects within MRDs are large-scale projects in which systems biology approaches are specifically applied to medically or clinically relevant topics.

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