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ICA Speaker: Prof. Josef Thalhamer, PhD.
University of Salzburg, Department of Molecular Biology
Hellbrunnerstr. 34, A-5020 Salzburg, Austria
ICA Secretary: Elisabeth Eppacher
Fax: +43-(0)662-8044-5751, Email: [email protected]
INTERNATIONAL PhD PROGRAM
Immunity in Cancer and Allergy – ICA
APPLICATION FORM
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If you have already obtained your degree, please scan the certificate and send a pdf-file.
Note: only diplomas and degrees equivalent to an Austrian Master's degree are acceptable.
Among these are German diplomas as well as Master's and Bachelor's Honours degrees
which include project work summarized in a written thesis (certain British or equivalent B. Sc.
Honours projects may also be acceptable).
Candidates who have not yet obtained their degree will be accepted if they can make
plausible that they will finish their studies within the next 6 months.
If you have already obtained a degree, please briefly specify in the space below the
occupation(s) you have pursued in the interim.
Additional Education (if applicable)
List additional Universities/colleges where you have earned a degree
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Give a summary in tabular form of your education and training at the university, college, etc.
(please do not exceed one page).
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Please list the courses you have taken and the grades obtained. Include all university level or
other relevant courses. If you have passed final university examinations, please provide
details (do not exceed one page).
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If you have any research experience, please list the techniques/methods you have learned
and describe the nature of the project and your contribution (please do not exceed one
page.)
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List of Publications/Abstracts/Presentation at Meetings (if applicable)
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Scientific interests
Write a short essay about the area of research (within the scope of the ICA program) that you
find most interesting (please do not exceed 300 words).
Preferred research topics / research groups
In the Appendix of this application form (page 12) you find a short description of the thesis
projects available.
You have to select 2 thesis projects (briefly justify your choice).
Your first choice:
Your second choice:
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Honours, scholarships, prizes and awards
Please list any honours or awards that you feel relevant to this application. Include dates and
a short description.
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Indicate speaking, reading and writing ability (very high, high, moderate, low)
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Curriculum Vitae
(please do not exceed one page)
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References
Please list below the names and addresses of the two referees to whom you have forwarded
the recommendation form and who have agreed to write a letter of recommendation on your
behalf.
Note: The letters of recommendation are essential for your application which will not be
processed without them. It is your responsibility to ensure that the referees send their
recommendation on time.
Referee 1
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Referee 2
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How did you become aware of our PhD program ?
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or other (please specify)
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Appendix
ICA Thesis Projects
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Project 1 - workgroup Hans Brandstetter
Topic: Proteolytic processing of endocytosed antigens is a key step in the immune response
and, therefore, essential to understand the Th2 priming triggered by allergens. How the initial
proteolytic cleavages in the bona fide allergenic sensitizer Bet v 1 occur is mechanistically
puzzling, as these sites are inaccessible to the solvent. We have direct evidence that the
encounter complex formation with endosomal proteases, such as cathepsin S, induces a
conformational transition in the allergen, thereby exposing new vulnerable sites to proteases.
Additionally, we have recently shown that antigenic peptides can be resynthesized by the
peptide ligase activity of legumain with potentially significant impact on the immune
response.
Thesis project: Antigen processing by endolysosomal proteases and vacuolar ligases
We propose to stabilize the relevant complexes of proteases with allergens as well as of
ligases with allergen-derived peptides. These complexes will be enzymatically, functionally
and structurally characterized, including co-crystallization. By employing a multidisciplinary
approach we will further investigate new concepts of T-cell epitope complex formation in the
molecular, cellular and organismic context.
Project 2 - workgroup Fatima Ferreira
Topic: The complex interplay between allergenic proteins, the allergen source, the
environment, the route of exposure, and the human immune system determines the initiation
of the allergic sensitization in predisposed individuals. In this context, certain protein antigens
are thought to possess distinct molecular pattern(s), which render per se harmless antigens
into allergens. These molecular patterns/signatures are associated with a property called
“allergenicity”, which can be defined as the capacity of a protein antigen to induce the
production of specific IgE antibodies.
Thesis project: Identifying TH-polarizing signatures on allergenic molecules
Therefore, the current project focuses on the identification of such structural/molecular
signatures inherent to allergenic molecules. As model antigens, allergens from birch pollen
(i.e. the major allergen Bet v 1 and the minor allergens Bet v 2 and Bet v 4) as well as nonallergenic proteins from various sources (i.e. bacterial and eukaryotic proteins) will be
investigated in detail. By using a comprehensive array of physico-chemical methods, all
antigens will be characterized in terms of stability, structural features, and ligand-binding
abilities. By comparing the immune polarizing properties of the different antigens, we will
dissect and correlate molecular patterns leading to an IgE-mediated immune response. This
will be done using established cell culture systems as well as in vivo mouse models of
adjuvant-free sensitization. This project will contribute to the identification of molecular
pattern/signatures on protein antigens that are involved in TH-cell polarization and IgE
production, and ultimately, to a better understanding of how the allergic sensitization process
is initiated.
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Project 3 - workgroup Iris Gratz
Topic: Autoimmunity results from failure to distinguish between self and non-self. Our group
investigates the mechanisms of immune regulation in peripheral tissues, focusing on the
skin. Our work is based on the hypothesis that the balance between suppressive regulatory T
cells (Treg) and pathogenic effector T cells (Teff) determines the outcome of an (auto-)
immune response. The main goal of our research is to elucidate the role of Treg cells in
tissues and define the requirements for their generation, recruitment to the target tissue and
maintenance.
Thesis project: Generation of stable and suppressive regulatory T cells
Apoptosis has recently been shown to be a factor that influences Treg:Teff-balance upon
persistent stimulation. Continual T cell receptor stimulation induced the expression of Foxp3
and demethylation of Treg specific genes (indicating the formation of stable Treg cells),
which implied that continued T cell stimulation favors Treg generation. However, this process
could only occur when activation-induced cell death was overcome. We now want to test the
hypothesis that resistance to apoptosis is crucial for stable Treg formation. In this study we
will apply transgenic and knock-out mouse models of autoimmunity for mechanistic studies of
regulatory and inflammatory processes, and basic cellular survival functions (i.e. study T cellspecific deletions of effector cytokines, regulatory molecules and apoptosis genes). We will
place a special emphasis on studying epigenetic modifications of Treg specific genes that
result from our manipulations.
Project 4 - workgroup Richard Greil
Topic: B-cell chronic lymphocytic leukaemia (CLL) results from the accumulation of small
mature, slowly dividing, monoclonal B-lymphocytes. Factors that may contribute to the initial
development of CLL are still poorly understood. Current evidence suggests a role f or
antigenic selection and interaction with tumour specific T-cells. Furthermore the myeloid
compartment is suggested to have an important role for the pathogenesis of this disease. In
this project we study how the myeloid and T cell compartment influences CLL
pathophysiology.
Thesis project: The influence of the myeloid compartment for CLL pathogenesis
The myeloid compartment in CLL patients is suggested to support the CLL B-cells by
generating a tumor-supportive and immunosuppressive niche. Myeloid cells (e.g. monocytes
and macrophages, dendritic cells,…) are a complex network of immune cells that is crucial
for proper function of the innate and adaptive immunity. It could be shown that macrophages
can be skewed into a variety of immunosuppressive phenotypes (Tumor-associated
macrophages (TAMs) and Myeloid-derived suppressor cells (MDSCs)). Since MDSCs are
potent inhibitors of T-cell responses they can limit intrinsic anti-tumor immune reactivity and
immune therapeutic approaches.
Therefore we will explore in-vitro and in-vivo the reestablishment of anti-cancer immunity in
CLL by using different murine model systems (e.g. Eµ-TCL1 mice). Consequently, we will
analyze alterations in T-cell subsets and their interactions with other immune cells.
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Project 5 - workgroup Tanja Hartmann
Topic: The lymphoid tumor microenvironment is of utmost importance for the
pathophysiology of chronic lymphocytic leukemia (CLL). As proliferation and survival of CLL
cells strongly depends on their transient residence in lymphoid organs, it is critical to
understand the mechanisms guiding CLL cell trafficking in the body. In this project we study
how microenvironmental signals are integrated in adhesive and migratory cues involved in
homing, retention and mobilization of CLL cells.
Thesis project: Functional alterations of homing receptor in CLL by tissue-specific
factors and therapy
Chemokine receptors such as CXCR4 and adhesion molecules such as VLA-4 and CD44
are key factors of CLL cell extravasation, motility and survival and will be addressed in this
project. The extent of expression of these factors on CLL cells critically influences the
prognosis of the patients and they represent therapeutic targets.
To analyze alterations in these molecules, we will employ in vitro and in vivo cell biological
and migration assays and mouse models to understand how tumor cell residing in various
organs impacts on adhesion molecule function. Short term homing and engraftment
experiments by transplantation of murine leukemic cells into wildtype mice will allow the
functional definition of these alterations and experimental therapeutic approaches. The
combination with videomicroscopical and immunohistochemical approaches will further
deepen the mechanistical insights.
Project 6 - workgroup Christian Huber
Topic: Cancer stem cells (CSCs) represent a very small subset of the tumor bulk with highly
malignant properties. CSCs are responsible for tumor initiation, growth and metastasis,
making them promising targets for innovative cancer therapies. In order to reveal molecular
markers and determinants of CSCs, we employ highly metastatic pancreatic cancer cell lines
and study their biological behavior using wholistic omics technologies. Pancreatic CSCs are
enriched in three-dimensional spheroid cultures and characterized by means of proteomics
(PTX), transcriptomics (TCX), and metabolomics (MTX). Using the three technologies, 100500 differentially expressed genes/proteins/metabolites may be identified.
Thesis project: Systems biology of cancer stem cells
In this project we aim at studying the role of different kinases and specific kinase inhibitors in
the Hedgehog and WNT pathways, which are highly relevant for cancer. Phosphoproteome
analysis will assist in the identification of relevant biological singling cascades. Identified
marker genes/proteins/metabolites will help to better understand the functional role of the
kinases in tumor growth and progression. Omics analysis will be supplemented by biological
assays that validate the function of identified targets (cooperation with the tumor biology
group of Fritz Aberger).
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Project 7 - workgroup Angela Risch
Topic: Lung cancer is the most common cancer worldwide and the leading cause of cancerrelated death. The main risk factor is smoking and as a result of the exposure to carcinogens
lung tumorigenesis is driven by genetic events. However, in addition, altered epigenetic
regulation is now emerging as a key factor in tumorigenesis. Epigenetic modifications
including DNA methylation, histone modifications and deregulated miRNAs, do not change
the DNA sequence but affect the regulation of gene expression. More importantly, epigenetic
alterations are established and modulated based on environmental stimuli. Monozygotic
twins offer a unique opportunity to determine environmentally induced and disease-relevant
alterations in genome-wide methylation patterns.
Thesis project: Inflammation-related epigenetic changes in lung carcinogenesis
Genome-wide methylation profiles (Illumina 450K) have just been obtained for peripheral
blood cell DNA from 25 monozygotic twin pairs, suffering from the chronic inflammatory lung
disease cystic fibrosis (CF) with varying degrees of disease discordance. This unique data
set will allow identification of loci with variable methylation correlating with inflammatory
disease status. The role of genes identified in the CF twin blood methylation profile as
candidate risk genes for the development of lung cancer will be investigated utilizing existing
clinical cohorts and banked normal lung and tumor tissues. Genes will be investigated for
epigenetic, genetic and transcriptional alterations and subsequently, in vitro, by functional
studies, including methylation specific luciferase promoter assays, siRNA knockdown,
proliferation and migration assays.
Project 8 - workgroup Josef Thalhamer
Topic: Various dendritic cell (DC) subsets of the skin display diverse functionality and thus
can influence downstream immune effector functions in different ways. The underlying
mechanisms primarily are differential sensitivity to, and subset-specific orchestration of
danger signals (PAMPs and DAMPs).
In contrast, antigen-inherent properties and their role in shaping immune reactions have
been largely left unnoticed. Based on recent data from our own laboratory, we hypothesize
that intrinsic molecular features of proteins lead to a different handling by distinct DC subsets
and thus results in protein-inherent modulation of the resulting immune response.
Thesis project: Protein-inherent features triggering different immune responses in
different dendritic cell subsets
Hitherto undefined properties that are intrinsic to the protein antigen can influence the
magnitude and type of effector mechanisms by differential engagement of distinct DC
subsets. Transgenic mice, with a manipulated DC composition in the skin, i.e. lacking
epidermal Langerhans cells (LC) and their langerin-positive counterpart in the dermis,
respond in fundamentally different ways to two widely-used model vaccines (OVA and ßgal). Gene vaccines encoding the antigen were used to ensure identical conditions for the
used antigens. Under these conditions, it became obvious that skin DCs can have different
selectivity for different protein antigens. The proposed thesis project will investigate a larger
panel of antigens, among them clinically relevant allergens, with the aim to identify proteininherent features which may define the selective interactions with certain subsets of skin
DCs. In addition, the role of processes upstream of immune effector functions, such as
antigen uptake, processing and presentation will be investigated. A comprehensive
knowledge of these processes will promote our current understanding of skin immunity, and
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will open novel approaches for the design of protective and therapeutic vaccines against
allergic disease.
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