Cancer Research - Europa

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Regulatory Genomics Advanced Genomics Instruments, Technology and Methods for Determination of Transcription Factor Binding Specialities; Applications for Identifi cation of Genes Predisposing to Colorectal <strong>Cancer</strong> Summary Determination of the sequence of the human genome, and knowledge of the genetic code through which mRNA is translated, have allowed rapid progress in the identifi cation of mammalian proteins. However, less is known about the molecular mechanisms that control the expression of genes. This project sets out to address this problem by developing novel tools and methods for analysing the specifi city of transcription factors to bind to particular sequences of DNA. Problem Not enough is known about the molecular mechanisms that control expression of human genes, and about the variations in gene expression that underlie many pathological states, including cancer. This is caused in part by a lack of information about the second genetic code – binding specifi cities of transcription factors (TFs). Deciphering this regulatory code is critical for cancer research, as little is known about the mechanisms by which the known genetic defects induce the transcriptional programs that control cell proliferation, survival and angiogenesis. In addition, changes in binding of transcription factors caused by single nucleotide polymorphisms (SNPs) are likely to be a major factor in many quantitative trait conditions, including familial predisposition to cancer. Aim The objective is to develop novel genomics tools and methods for the determination of transcription factor binding specifi city. These tools will be used for the identifi cation of regulatory SNPs that predispose to colorectal cancer, and for characterisation of downstream target genes that are common to multiple oncogenic TFs. 68 Keywords | Genomics | molecular genetics | transcription factors | The specifi c aims are: • to develop novel high throughput multiwell-plate and DNA-chipbased methods for determination of TF binding specifi city; • to determine experimentally the binding specifi cities of known cancer- associated TFs; • to predict computationally, and to verify experimentally, elements that are regulated by these TFs in genes that are essential for cell proliferation; • to develop a SNP genotyping chip composed of SNPs that aff ect the function of TF-binding sites conserved in mammalian species; • to use this chip for the genotyping of patients with hereditary cancer predisposition as well as controls in three European populations, for identifi cation of regulatory SNPs associated with cancer. Expected results This project aims to understand the basic principles involved in growth regulation by oncogenic TFs, and is expected to have a major impact in the understanding of cancer. Identifi - cation of SNPs associated with low penetrance cancer predisposition would be a major breakthrough in the eff ort to understand inheritance of quantitative trait loci, and will have implications on the population’s healthcare. The methods developed within the project ( 1) have already allowed genome-scale prediction of regulatory elements in the human genome, and the methods developed should make feasible the analysis of DNAbinding specifi cities of all TFs, and consequently signifi cantly improve our understanding regulation of gene expression. Potential applications We expect that the project will lead to the identifi cation of genes that associate with colorectal cancer. This will have direct implications on diagnosis and treatment of a cancer type that aff ects more than 200 000 Europeans every year. Methods, tools and instrumentation for advanced genomics developed within this project will improve EU scientifi c competitiveness in the rapidly developing fi eld of regulatory genomics, and will allow EU scientists to be in a very good starting position to decipher the genetic code controlling regulation of gene expression. (1) Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, Taipale J, Genomewide Prediction of Mammalian Enhancers Based on Analysis of Transcription- Factor Binding Affi nity. Cell. 124:47-59, 2006. CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
A high-throughput assay of transcription factor binding specifi city developed within the Regulatory genomics project (Hallikas et al., Cell 124:47-59, 2006). Coordinator Jussi Taipale University of Helsinki Molecular/<strong>Cancer</strong> Biology Programme Helsinki, Finland jussi.taipale@helsinki.fi Partners Jörg Hoheisel Deutsches Krebsforschungszentrum Functional Genome Analysis Heidelberg, Germany j.hoheisel@dkfz.de Markus Beier Febit biotech gmbh Heidelberg, Germany markus.beier@febit.de BIOLOGY Torben Ørntoft Aarhus University Hospital Dept. of Clinical Biochemistry Aarhus N, Denmark orntoft@ki.au.dk Jan Lubinski Pomeranian Medical University Szczecin, Poland lubinski@sci.pam.szczecin.pl Admin. contact: ziebab@sci.pam.szczecin.pl Project number LSHG-CT-2004-512142 EC contribution € 2 200 000 Duration 48 months Starting date 01/09/2004 Instrument STREP Project website research.med.helsinki.fi / regulatorygenomics/ 69
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PROJECT SYNOPSES CANCER RESEARCH PR
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CANCER RESEARCH PROJECTS FUNDED UND
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TABLE OF CONTENTS FOREWORD - CANCER
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Prevention 97 EPIC 98 EUROCADET 100
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CANCER: COMBATING A COMPLEX DISEASE
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Biology Cancer is a disease ethat t
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p53 activators ASPP Partner 5 NFkap
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Keywords | Angiogenesis | vasculoge
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Keywords | Tumour-host interactions
Page 19 and 20: Keywords | Breast | metastasis | ge
Page 21 and 22: Keywords | Identifi cation of novel
Page 23 and 24: Keywords | Systems biology | modell
Page 25 and 26: Keywords | Oncology | anticancer th
Page 27 and 28: • public health research coupled
Page 29 and 30: Expected results We will construct
Page 31 and 32: Potential applications Our DNA is u
Page 33 and 34: Microscopic examination of tissue s
Page 35 and 36: Pluripotent embryonic stem cells ar
Page 37 and 38: • Decryption of the leukaemia cel
Page 39 and 40: • identifi cation of molecular ta
Page 41 and 42: A B C LT-HSC CSC The Cancer Stem Ce
Page 43 and 44: X-ray diff raction of target drug c
Page 45 and 46: using pathway-specifi c reporter ce
Page 47 and 48: Keywords | Kinases | pediatric panc
Page 49 and 50: Keywords | Lymphangiogenesis | angi
Page 51 and 52: Keywords | Breast cancer | metastas
Page 53 and 54: Keywords | Mitosis | phosphorylatio
Page 55 and 56: Keywords | Therapy | genome | telom
Page 57 and 58: Keywords | Multiple myeloma | cance
Page 59 and 60: Keywords | p53 tumour suppressor |
Page 61 and 62: Development of eff ective anti-canc
Page 63 and 64: Coordinator Patrick A. Curmi INSERM
Page 65 and 66: Drosophila as a model system for tu
Page 67 and 68: Normal cell growth and epithelial l
Page 69: effi ciently with cancer cell proli
Page 73 and 74: Coordinator Ewa Sikora Nencki Insti
Page 75 and 76: Expected results The SIROCCO consor
Page 77 and 78: Keywords | Epigenetics | gene regul
Page 79 and 80: Keywords | Hereditary | tricarboxyl
Page 81 and 82: Keywords | HSV-1 | hepatocellular c
Page 83 and 84: Keywords | Apoptosis | autophagy |
Page 85 and 86: Keywords | Tumour | host | signalli
Page 87 and 88: Aetiology The uncontrolled cell gro
Page 89 and 90: Coordinator Rosalind Eeles Reader i
Page 91 and 92: The parallelogram approach in CARCI
Page 93 and 94: Keywords | Melanoma | genetics | na
Page 95 and 96: Keywords | Virus | bacteria | HPV |
Page 97 and 98: Keywords | Breast | prostate | gene
Page 99 and 100: Prevention The fact that preventing
Page 101 and 102: Coordinator Elio Riboli Imperial Co
Page 103 and 104: Coordinator Jan Willem Coebergh Joh
Page 105: Coordinator Jose M a Benlloch Conse
Page 108 and 109: BAMOD Breath-Gas Analysis for Molec
Page 110 and 111: BioCare Molecular Imaging for Biolo
Page 112 and 113: These centres of excellence will in
Page 114 and 115: Expected results Optimise the benef
Page 116 and 117: 114 Cell proliferation and apoptosi
Page 118 and 119: COBRED Colon and Breast cancer Diag
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DASIM Diagnostic Applications of Sy
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Expected results Primarily, the res
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Coordinator John A. Foekens Dept. o
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124 Aim Drop-Top has two major obje
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Coordinator Gorka Ochoa Progenika B
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Expected results The E.E.T.-Pipelin
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e developed by eTUMOUR is likely to
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Coordinator Angel Porgador Ben-Guri
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• the design of a compact assembl
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Potential applications We believe t
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Tumor initiation, progression to ma
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MolDiag-Paca Novel Molecular Diagno
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NEMO Nano based capsule-Endoscopy w
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OVCAD Ovarian Cancer - Diagnosis of
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P-MARK Validation of recently devel
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POC4life Multiparametric quantum do
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PROMET Prostate cancer molecular-or
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Micrometastasis in the bone marrow.
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and pharmaco-kinetics studies. This
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Coordinator Raffaella Giavazzi Isti
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• Development of tools for diagno
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Treatment Two major problems when t
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Coordinator Lluis M. Mir UMR 8121 C
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Potential applications ANGIOSTOP ha
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Green-fl uorescence protein- expres
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Coordinator Robert Hawkins Universi
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Expected results The BACULOGENES pr
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descriptors of the molecules to be
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Keywords | Therapeutic vaccine | im
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Keywords | Cancer chemotherapy | dr
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Keywords | Children | cancer | leuk
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Chimaeric TCR shown in context of n
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Andrea Splendiani Leaf Bioscience s
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Coordinator Anne O’Garra The Medi
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Coordinator Jacques Bartholeyns IDM
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Structure Driven Drug Design The in
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• acquire fundamental knowledge a
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Terry Jones Victoria University of
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Potential applications The use of t
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groups and management structures. T
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T. Barbui Azienda Ospedaliera-Osped
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Keywords | Mantle cell lymphoma | t
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Keywords | Hypoxia | HIF | pericell
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Keywords | Radiation-induced compli
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Keywords | Gene therapy | adenoviru
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Keywords | Dependence receptors | a
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Keywords | Photodynamic therapy | a
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Keywords | Ovarian cancer | thymidy
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Keywords | Quality assurance | clin
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Keywords | Circadian | clocks | cel
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Keywords | Anticancer therapy | onc
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Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
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Keywords | Solid tumours | apoptosi
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Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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Indices - Keywords Indices - Partne
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● disease markers 131 ● DNA dam
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● renal 77 ● replication 219
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Bos, Nico A. 56 Boskovic, Darinka 2
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Geley, Stephan 159 Georgopoulos, Li
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Lingner, Joachim 54 Linial, Michal
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Ragno, Pia 115 Rainford, Martyn 92
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Vernos, Isabelle 22 Veronesi, Umber
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● Centre Hospitalier Universitair
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● IFOM - Fondazione Istituto FIRC
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● National University of Ireland
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● University of Bari 174 ● Univ
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