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EPISTEM Role of p63 and Related Pathways in Epithelial Stem Cell Proliferation and Diff erentiation and in Rare EEC-Related Syndromes Summary The focus of EPISTEM is to generate new knowledge and translate it into applications that enhance human health. To this end both fundamental and applied research will be involved. EPISTEM integrates multidisciplinary and coordinated eff orts to understand the molecular basis of factors involved in epidermal stem cell generation, maintenance and diff erentiation and skin disease. Moreover, the core molecule that will be studied in this Integrated Project is p63 (and related pathways), a molecule genetically proven to be involved in the development of rare skin diseases. Collectively, the prevalence of ectodermal dysplasia syndromes (EDS) is estimated at seven cases in 10 000 births. Currently there is no cure for these patients. By creating the EPISTEM consortium, we want to address, from diff erent angles (i.e. via genetics, gene profi ling, molecular and cellular biology, structural biology, drug design and bioinformatics), the molecular pathways involved in epidermal dysplasia syndromes making use of diff erent technologies (mutation analysis, micro-array, ChiP, transgenes, proteomics, in vitro skin cultures, crystallography, etc.). Our consortium brings together leading European clinicians, geneticists, molecular and cellular biologists, structural biologists, a drug designer and bioinformatics specialists in the fi eld of p63 (and related molecules) research. Problem The core molecule that will be studied by the EPISTEM consortium is p63 (and related pathways), a molecule genetically proven to be involved in the development of rare skin diseases such as EEC syndrome (Ectrodactyly-ectodermal dysplasia – clefting), Hay-Wells (AEC) syndrome, Limb-mammary syndrome, ADULT syndrome, Rapp-Hodgkin syndrome and non-syndromic split hand-split foot malformation. Currently there is no cure for these patients. 32 Keywords | Epithelial stem cell | keratinocyte diff erentiation | p63 and family members | EEC-related syndromes | Aim • Collecting and culturing of keratinocytes from EDS patients with p63 mutations and extensive analysis of phenotype-genotype correlation. These keratinocytes will be used to uncover the role of p63 proteins and pathways in normal and abnormal skin development. • Building relevant in vitro and in vivo skin disease models for studying the role of p63 in EDS disease and the genetic assessment of novel pathways discovered during this project. These models will also be used for drug assessment. • Provide insight into the regulation and involvement of p63 and related pathways in skin diff erentiation, the maintenance of the proliferative capacity of epithelial stem cells and the transition of ectodermal cells to epidermal stem cells. • Screening for, and design of, novel therapeutic drugs, based on three-dimensional p63 models, that will refold/ reactivate or inhibit p63 mutants and induce biological responses in relevant disease models. Expected results First of all, the EPISTEM consortium will generate a thorough insight into the molecular biology of a rare disease such as EDS, for which no cure is currently available. Secondly, characterising and understanding how epidermal stem cell maintenance is regulated by p63 could be benefi - cial for the treatment of burn victims since these stem cells could be used for tissue regeneration. So, in the long run, the EPISTEM research proposal may have a far broader impact on clinical practice and the biomedical industry than is currently estimated. Thirdly, this integrated project will generate knowledge and technology that is not only applicable to p63 itself, but also to its family members p53 and p73; p53 is an important target that is mutated in most cancers and p73 is an important molecule for neurogenesis. Finally, from a technological point of view, the EPISTEM proposal will invest in the development of chIP (chromatin immunoprecipitation) on chip technology. Potential applications Drug-development for the cure of skin diseases, cancer, etc. and a wound-healing treatment. CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Pluripotent embryonic stem cells are cultivated on glass coverslips coated with fi broblast-secreted matrix proteins (and probably trapped growth factors and cytokines). Undiff erentiated ES cells are induced to diff erentiate by removal of LIF (Leukaemia Inhibitory Factor) and the addition of BMP-4 (Bone Morphogenetic Protein-4). These cells were transfected with transduction-competent (TAp63) and transduction-incompetent (Np63) expression vectors. The presence of ES-derived keratinocytes is scored using an antibody against the cytokeratin-14 intermediate fi lament. These experiments show that TAp63 is capable of inducing keratinocyte diff erentiation starting from a stem cell population. Which cellular programmes are involved in this process remains to be determined. Coordinator Peter Vandenabeele Flanders Interuniversity Institute for Biotechnology Gent, Belgium peter.vandenabeele@dmbr.ugent.be wim.declercq@dmbr.ugent.be jelle.verspurten@dmbr.ugent.be Partners Hans van Bokhoven Gijs Schaftenaar Martijn Huynen Radboud University Nijmegen Nijmegen, The Netherlands h.vanbokhoven@antrg.umcn.nl g.schaftenaar@cmbi.ru.nl huynen@cmbi.ru.nl BIOLOGY Gerry Melino Vincenzo De Laurenzi Università degli Studi di Roma Tor Vergata Rome, Italy melino@uniroma2.it delaurenzi@uniroma2.it Gian Paolo Dotto University of Lausanne Lausanne, Switzerland gdotto@partners.org John McGrath King’s College London London, United Kingdom john.mcgrath@kcl.ac.uk Klas Wiman Karolinska Institutet Stockholm, Sweden klas.wiman@cck.ki.se Volker Doetsch J.W. Goethe-Universität Frankfurt am Main Frankfurt, Germany vdoetsch@em.uni-frankfurt.de Roberto Mantovani Università degli Studi di Milano Milan, Italy mantor@unimi.it M. Gulisano Istituto Oncologico del Mediterraneo Viagrande, Italy m.gulisano@iomricerca.it Project number LSHB-CT-2005-019067 EC contribution € 8 130 000 Duration 48 months Starting date 01/01/2006 Instrument IP Project website www.epistem.be Daniel Aberdam Institut National de la Santé et de la Recherche Médicale Nice, France aberdam@unice.fr Luca Lorenzi GeneSpin SrL Milano, Italy luca.lorenzi@genespin.com Pongsak Angkasith Chiang Mai University Chiang Mai, Thailand Xie Sheng-Wu Shanghai Jiaotong University Shanghai, China 33
Page 1 and 2: PROJECT SYNOPSES CANCER RESEARCH PR
Page 3 and 4: CANCER RESEARCH PROJECTS FUNDED UND
Page 5 and 6: TABLE OF CONTENTS FOREWORD - CANCER
Page 7 and 8: Prevention 97 EPIC 98 EUROCADET 100
Page 9 and 10: CANCER: COMBATING A COMPLEX DISEASE
Page 11 and 12: Biology Cancer is a disease ethat t
Page 13 and 14: p53 activators ASPP Partner 5 NFkap
Page 15 and 16: Keywords | Angiogenesis | vasculoge
Page 17 and 18: 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: Microscopic examination of tissue s
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 and 70: effi ciently with cancer cell proli
Page 71 and 72: A high-throughput assay of transcri
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
Page 120 and 121:
DASIM Diagnostic Applications of Sy
Page 122 and 123:
Expected results Primarily, the res
Page 124 and 125:
Coordinator John A. Foekens Dept. o
Page 126 and 127:
124 Aim Drop-Top has two major obje
Page 128 and 129:
Coordinator Gorka Ochoa Progenika B
Page 130 and 131:
Expected results The E.E.T.-Pipelin
Page 132 and 133:
e developed by eTUMOUR is likely to
Page 134 and 135:
Coordinator Angel Porgador Ben-Guri
Page 136 and 137:
• the design of a compact assembl
Page 138 and 139:
Potential applications We believe t
Page 140 and 141:
Tumor initiation, progression to ma
Page 142 and 143:
MolDiag-Paca Novel Molecular Diagno
Page 144 and 145:
NEMO Nano based capsule-Endoscopy w
Page 146 and 147:
OVCAD Ovarian Cancer - Diagnosis of
Page 148 and 149:
P-MARK Validation of recently devel
Page 150 and 151:
POC4life Multiparametric quantum do
Page 152 and 153:
PROMET Prostate cancer molecular-or
Page 154 and 155:
Micrometastasis in the bone marrow.
Page 156 and 157:
and pharmaco-kinetics studies. This
Page 158 and 159:
Coordinator Raffaella Giavazzi Isti
Page 160 and 161:
• Development of tools for diagno
Page 163 and 164:
Treatment Two major problems when t
Page 165 and 166:
Coordinator Lluis M. Mir UMR 8121 C
Page 167 and 168:
Potential applications ANGIOSTOP ha
Page 169 and 170:
Green-fl uorescence protein- expres
Page 171 and 172:
Coordinator Robert Hawkins Universi
Page 173 and 174:
Expected results The BACULOGENES pr
Page 175 and 176:
descriptors of the molecules to be
Page 177 and 178:
Keywords | Therapeutic vaccine | im
Page 179 and 180:
Keywords | Cancer chemotherapy | dr
Page 181 and 182:
Keywords | Children | cancer | leuk
Page 183 and 184:
Chimaeric TCR shown in context of n
Page 185 and 186:
Andrea Splendiani Leaf Bioscience s
Page 187 and 188:
Coordinator Anne O’Garra The Medi
Page 189 and 190:
Coordinator Jacques Bartholeyns IDM
Page 191 and 192:
Structure Driven Drug Design The in
Page 193 and 194:
• acquire fundamental knowledge a
Page 195 and 196:
Terry Jones Victoria University of
Page 197 and 198:
Potential applications The use of t
Page 199 and 200:
groups and management structures. T
Page 201 and 202:
T. Barbui Azienda Ospedaliera-Osped
Page 203 and 204:
Keywords | Mantle cell lymphoma | t
Page 205 and 206:
Keywords | Hypoxia | HIF | pericell
Page 207 and 208:
Keywords | Radiation-induced compli
Page 209 and 210:
Keywords | Gene therapy | adenoviru
Page 211 and 212:
Keywords | Dependence receptors | a
Page 213 and 214:
Keywords | Photodynamic therapy | a
Page 215 and 216:
Keywords | Ovarian cancer | thymidy
Page 217 and 218:
Keywords | Quality assurance | clin
Page 219 and 220:
Keywords | Circadian | clocks | cel
Page 221 and 222:
Keywords | Anticancer therapy | onc
Page 223 and 224:
Coordinator Monika Lusky Transgene
Page 225 and 226:
6 000 women over a three-year perio
Page 227 and 228:
Keywords | Solid tumours | apoptosi
Page 229 and 230:
Keywords | Lymphoma | leukaemia | v
Page 231:
Coordinator Riccardo Dolcetti Centr
Page 234 and 235:
CCPRB Cancer Control using Populati
Page 236 and 237:
EPCRC The European Palliative Care
Page 238 and 239:
EUROCAN+PLUS Feasibility Study for
Page 240 and 241:
EUSTIR A European strategy for the
Page 242 and 243:
NORMOLIFE Development of new therap
Page 245 and 246:
Scientifi c Model Systems The compl
Page 247 and 248:
Performance of benchmarking exercis
Page 249 and 250:
• markers correlating with the im
Page 251 and 252:
Indices - Keywords Indices - Partne
Page 253 and 254:
● disease markers 131 ● DNA dam
Page 255 and 256:
● renal 77 ● replication 219
Page 257 and 258:
Bos, Nico A. 56 Boskovic, Darinka 2
Page 259 and 260:
Geley, Stephan 159 Georgopoulos, Li
Page 261 and 262:
Lingner, Joachim 54 Linial, Michal
Page 263 and 264:
Ragno, Pia 115 Rainford, Martyn 92
Page 265 and 266:
Vernos, Isabelle 22 Veronesi, Umber
Page 267 and 268:
● Centre Hospitalier Universitair
Page 269 and 270:
● IFOM - Fondazione Istituto FIRC
Page 271 and 272:
● National University of Ireland
Page 273 and 274:
● University of Bari 174 ● Univ
Page 275 and 276:
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