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Project descriptions JCF call December 2014 / January 2015

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Project 1

Project leader:

Joachim Kunz, Andreas Kulozik

Affiliation:

MMPU Group Molecular Pediatric Oncology, Heidelberg.
EMBL and
Children’s Hospital, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg

Start of MD project:

1 April 2015 (± 2 months)

Project description

Title:

Acute T-lymphoblastic leukemia

Summary:

Acute T-lymphoblastic leukemia (T-ALL) is a common malignancy in childhood that, with modern treatment, can be cured in approximately 80% of patients. However, patients that experience a relapse face a dismal prognosis because relapsed T-ALL frequently is refractory to treatment.
Our leukemia group focusses on two aspects:
With the help of a large collection of well characterized patient samples we aim at identifying molecular parameters that predict the risk of relapse. To this ends, we use next generation sequencing, Sanger sequencing, multiplex ligation dependent probe amplification (MLPA) and methylome analysis (Illumina 450 k array). The identification of molecular risk markers could allow for an early and risk adapted stratification of treatment, preventing treatment toxicity in the low risk group and relapses in the high risk group.
Second, we want to functionally characterize mechanism resulting in leukemogenesis and in leukemia relapse. Together with the Dirk Grimm group we have established an AAV transduction system that allows us to knock down and overexpress candidate oncogenes and tumor suppressor genes in T-ALL cell lines. Using this method we can functionally validate putative leukemia driver genes that we identified by genetic analysis of primary and relapsed T-ALL.

References:

The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse.

Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE.

Haematologica. 2014 Oct;99(10):e188-92. doi: 10.3324/haematol.2014.104992. Epub 2014 Jun 27. No abstract available.

Notch1 activation clinically antagonizes the unfavorable effect of pten inactivation in bfm-treated children with precursor t-cell acute lymphoblastic leukemia.
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, Koehler R, Muckenthaler MU, Kulozik AE
Haematologica 2013 Jun;98:928-936

Website:

Pediatric Oncology, Hematology, Immunology and Pulmonology

Methods:

Sanger Sequencing, Next Generation Sequencing, 450k array, MLPA, cell culture, viral transduction, Western blot, PCR, RT-PCR

Cooperation partners:

Jan Korbel, EMBL Genome Biology
Dirk Grimm, Bioquant Viral transduction
Jean-Pierre Bourquin, Zürich (leukemia xenograft model)

Contact:

joachim.kunz@med.uni-heidelberg.de

Project 2

Project supervisor:

Jan Siemens

Affiliation:

Department of Pharmacology, Heidelberg University

Siemens lab

Start of MD project:

Spring / summer of 2015

Project description: 

Title:

The Role of Mast Cells in Inflammatory and Neuropathic Pain

Summary:

Pain serves an important function to facilitate protective reflexes in order to prevent tissue damage and to promote healing. However, persistent (chronic) forms of debilitating pain are a huge burden to patients and society.     
Immunological responses and inflammatory mediators play an important role in modulating pain signals that are generated by peripheral sensory neurons. A large variety of different inflammatory mediators (the so called “inflammatory soup”) sensitize nociceptive neurons resulting in decreased pain thresholds. However, the source of the inflammatory mediators and their relative contribution to pain sensitization in the context of pathological pain states are largely unknown.     
Among the different immune cells, Mast cells appear to be prime candidates to modulate pain signals as they are frequently found in close proximity to nociceptive neurons. Additionally, Mast cells are a reservoir of a variety of different inflammatory mediators. A number of studies have implicated Mast cells in the pathology of persistent forms of pain. However, the lack of a specific Mast cell model limits the conclusions that can be drawn from these studies.  
 
Here, using a mouse line specifically depleted of Mast cells, this project aims to elucidate the role Mast cells in models of inflammatory and neuropathic pain.

References:

Mast cells: Versatile gatekeepers of pain, Mol Immunol. 2014, S0161-5890(14)00054-6

Cre-Mediated Cell Ablation Contests Mast Cell Contribution in Models of Antibody and T Cell-Mediated Autoimmunity, Immunity 2011, 35, 832–844

MMPU Website:

Research Group Chronic Pain

Methods:

Behavior experiments  (pain response measurements) using Mast cell deficient mice

Cooperation partners:

Hans-Reimer Rodewald, DKFZ

Personal Qualifications:

We are looking for an enthusiastic candidate with an interest in sensory neuroscience at the interface with Immunology. Previous experience in the handling of laboratory animals (rodents) would be an asset. The willingness to learn and carry out animal experiments is required.

Keywords:

Mast cells; Pain; Sensory Neurons, Cytokines; Neuro-Immune Interactions

Contact:

Ulrike Baur-Finck