Creation Of A PDGF-C Autocrine Loop By HIC1 Inactivation
Brian R Rood
Children s National Medical Center Washington, Dc 20010
Grant 1K08NS051477-01A2 from National Institute Of Neurological Disorders And Stroke IRG: NST
Abstract: Brian R. Rood, MD is an Assistant Professor of Pediatrics at the Children s National Medical Center. Dr. Rood has shown the importance of chromosome 17p deletion and epigenetic inactivation in the silencing of the tumor suppressor gene HIC-1 in medulloblastoma. With the support of an Avery Research Scholars Award from the Children s Research Institute, Dr. Rood used gene expression profiling to identify potential targets of HIC-1 mediated transcriptional repression. He has also begun using siRNA to silence HIC-1 in order to confirm one of these targets, PDGF-C. With the support of a Mentored Clinical Scientist Development Award, Dr. Rood plans to use this strategy to demonstrate the role of HIC-1 inactivation in the establishment of a growth stimulatory autocrine loop involving PDGF-CC. The Specific Aims of this project are 1) To evaluate medulloblastoma cell lines for the presence of PDGF-CC autocrine activity, 2) To investigate the mechanism of HIC1 mediated PDGF-C repression and 3) To determine whether HIC1 inactivation establishes an autocrine signaling loop and identify the receptors activated by PDGF-CC. Dr. Rood will obtain the technical skills and guidance necessary to carry out this investigation with co-mentorship from three sources Dr. Stephan Ladisch, an expert in tumor biology, Dr. Vottorio Gallo, a leading expert in neural stem cell signaling and biology, and Dr. Jeffrey Toretsky, an expert in tumor signal transduction. With the additional resources and formal training provided by the Career Development Program established at CNMC, the short-range scientific goals of this project can be accomplished. With additional guidance by Dr. Roger Packer, a renowned clinical neuro-oncologist, Dr. Rood will develop an independent career in translational research within 5 years. The long-range goal of this work is to broaden the understanding of brain tumorigenesis to foster the development of novel targeted therapies. Brain Tumors are the number one cause of cancer related death in children. Current therapies, effective in a minority of malignant tumors, are very toxic and leave children with significant long term sequelae. An era of targeted, relatively non-toxic, molecular therapies is just beginning and greater understanding of the molecular biology of brain tumors is required to develop these agents. This project seeks to investigate the biologic role of one of these potential therapeutic targets, the PDGF signaling pathway.
Keywords: autocrine, neoplasm /cancer, CpG island, DNA, DNA methylation, biological signal transduction, biology, brain, career, cell, cell line, children, chromatin immunoprecipitation, chromosome, chromosome deletion, colon neoplasm, conditioning, death, epigenetics, fibroblast, gene, gene expression profiling, genetically modified animal, growth factor, growth media, human, laboratory mouse, lead, ligand, liver, loss of heterozygosity, lung, mammary gland, measurement, medulloblastoma, model, molecular biology, pediatrics, platelet, protein, receptor, repression, role, stem cell, teacher, therapy, training, tumor suppressor gene
Project start date: 2007-04-09
Project end date: 2012-02-28
1K08NS051477-01A2 (2007): $145800
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Brian R Rood
CREATION OF A PDGF-C AUTOCRINE LOOP BY HIC1 INACTIVATION
Brian R Rood
Children´s National Medical Center, Washington, Dc 20010
Grant 5K08NS051477-04 from National Institute Of Neurological Disorders And Stroke
Abstract: Brian R. Rood, MD is an Assistant Professor of Pediatrics at the Children´s National Medical Center. Dr. Rood has shown the importance of chromosome 17p deletion and epigenetic inactivation in the silencing of the tumor suppressor gene HIC-1 in medulloblastoma. With the support of an Avery Research Scholars Award from the Children´s Research Institute, Dr. Rood used gene expression profiling to identify potential targets of HIC-1 mediated transcriptional repression. He has also begun using siRNA to silence HIC-1 in order to confirm one of these targets, PDGF-C. With the support of a Mentored Clinical Scientist Development Award, Dr. Rood plans to use this strategy to demonstrate the role of HIC-1 inactivation in the establishment of a growth stimulatory autocrine loop involving PDGF-CC. The Specific Aims of this project are 1) To evaluate medulloblastoma cell lines for the presence of PDGF-CC autocrine activity, 2) To investigate the mechanism of HIC1 mediated PDGF-C repression and 3) To determine whether HIC1 inactivation establishes an autocrine signaling loop and identify the receptors activated by PDGF-CC. Dr. Rood will obtain the technical skills and guidance necessary to carry out this investigation with co-mentorship from three sources Dr. Stephan Ladisch, an expert in tumor biology, Dr. Vottorio Gallo, a leading expert in neural stem cell signaling and biology, and Dr. Jeffrey Toretsky, an expert in tumor signal transduction. With the additional resources and formal training provided by the Career Development Program established at CNMC, the short-range scientific goals of this project can be accomplished. With additional guidance by Dr. Roger Packer, a renowned clinical neuro-oncologist, Dr. Rood will develop an independent career in translational research within 5 years. The long-range goal of this work is to broaden the understanding of brain tumorigenesis to foster the development of novel targeted therapies. Brain Tumors are the number one cause of cancer related death in children. Current therapies, effective in a minority of malignant tumors, are very toxic and leave children with significant long term sequelae. An era of targeted, relatively non-toxic, molecular therapies is just beginning and greater understanding of the molecular biology of brain tumors is required to develop these agents. This project seeks to investigate the biologic role of one of these potential therapeutic targets, the PDGF signaling pathway
Keywords: 0-11 years old; 17p; 17p13.1; 17p13.3; 17q; Allelic Loss; Anti-Oncogenes; Antioncogenes; Apoptotic; Assay; Autocrine Communication; Autocrine Signaling; Autocrine Systems; Award; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological; Biological Assay; Biology; Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Breast; CHIP assay; Cancer Cause; Cancer Etiology; Cancer of Brain; Cancers; Cell Communication and Signaling; Cell Signaling; Cells; Cessation of life; ChIP (chromatin immunoprecipitation); Child; Child Youth; Childhood Brain Neoplasm; Childhood Brain Tumor; Children (0-21); Chromosome 17 Distal Arm; Chromosome 17 Long Arm; Chromosome 17 Proximal Arm; Chromosome 17 Short Arm; Chromosome 17p; Clinical; Cloning; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Conditioned Culture Media; Conditioned Medium; Coupled; CpG Islands; CpG-Rich Islands; Culture Media, Conditioned; DNA; DNA Methylation; DNA Molecular Biology; Data; Death; Deoxyribonucleic Acid; Development; Emerogenes; Encephalon; Encephalons; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Event; Exhibits; Fibroblasts; Fostering; Gene Down-Regulation; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; Gene Transcription; Generalized Growth; Genes; Genes, Cancer Suppressor; Genes, Onco-Suppressor; Genes, p53; Genetic Transcription; Goals; Growth; Human; Human, Child; Human, General; Hypermethylation; Incidence; Intracellular Communication and Signaling; Investigation; Knockout Mice; Left; Ligands; Liver; Loss of Heterozygosity; Lung; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Brain; Malignant neoplasm of brain; Man (Taxonomy); Man, Modern; Measurement; Mediating; Medical center; Mentored Clinical Scientist Development Award (K08); Mentored Clinical Scientists Development Award; Mentorship; Mice, Knock-out; Mice, Knockout; Minority; Molecular; Molecular Biology; Molecular Interaction; Nervous System, Brain; Neural Neoplasm; Neural Stem Cell; Neural Tumor; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Null Mouse; Oncogenes, Recessive; Oncogenes-Tumor Suppressors; Oncogenesis; Oncologist; Ovarian; P53; PDGF; PDGF Signaling Pathway; PDGF-C; PDGF-CC; PDGFR; Pathway interactions; Pediatric Neoplasm of the Brain; Pediatric Tumor of the Brain; Pediatrics; Phased Career Development; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Profilings, Gene Expression; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Proteins; RNA Expression; RNA, Small Interfering; Receptor Protein; Receptors, PDGF; Repression; Research; Research Institute; Research Resources; Resources; Respiratory System, Lung; Role; Signal Transduction; Signal Transduction Systems; Signaling; Small Interfering RNA; Source; TP53; TP53 gene; TRP53; Testing; Time; Tissue Growth; Training; Trans-Activation (Genetics); Transactivation; Transcript Expression Analyses; Transcript Expression Analysis; Transcription; Transcription Repression; Transcription, Genetic; Transcriptional Repression; Translational Research; Translational Research Enterprise; Translational Science; Tumor Biology; Tumor Protein p53 Gene; Tumor Suppressing Genes; Tumor Suppressor Genes; Work; autocrine; biological signal transduction; body system, hepatic; career; career development; children; chromatin immunoprecipitation; effective therapy; gene product; gene repression; malignancy; medulloblastoma; medulloblastoma cell line; mouse model; neoplasm/cancer; neoplastic; nerve stem cell; neural progenitor cells; neuronal progenitor; neuronal progenitor cells; novel; oncosuppressor gene; ontogeny; organ system, hepatic; pathway; platelet-derived growth factor C; professor; programs; pulmonary; receptor; response; siRNA; skills; social role; therapeutic target; translation research enterprise; tumor; tumorigenesis; tumors in the brain; youngster
Project start date: 2007-04-09
Project end date: 2012-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-00-003
5K08NS051477-04 (2010): $145800