Jansen Laboratory Research Interests
Recent technological advances in the analysis of gene sequence and activity (genomics) and protein expression (proteomics) allow the monitoring of thousands of targets at a time. The vast amount of data generate in such experiments can be overwhelming and specialized statistical and computational tools are required to extract meaningful information. The focus of this laboratory is the analysis of genetic and genomic data. Several ongoing project and collaborations use the Affymetrix microarray platform to collect genomic DNA sequence data and study genome-wide RNA expression.
Of specific interest to is the function of Rho GTPases. These molecular switches trigger a large variety of cellular responses including cytoskeletal changes, cell cycle control and transcription. Rac proteins, members of the Rho GTPase family, are best known for their involvement in reorganization of the cytoplasmic actin structure in response to extracellular stimuli. The Rac group of proteins consists of three highly homologous members. Whereas Rac1 and Rac3 are widely expressed, Rac2 expression is restricted to hematopoietic cells. Deficiency of one or more of these proteins has been demonstrated to lead to multiple cellular defects in hematopoietic stem/progenitor cells (HS/PC). Purification/Enrichment of hematopoietic cells is achieved by high speed sorting of bone marrow cells, a service provided by the Flow Cytometry Core (Dan Marmer). We are using bone marrow derived subpopulations for microarray experiments to elucidate the function of Rac GTPases in the function of stem cells and erythropoiesis on the transcriptional level. This work is done in close cooperation with Cincinnati Children's Affymetrix Core Facility (Dr. Steven Potter) and the Division of Pediatrics Informatics (Dr. Bruce Aronow).
Similarly we are trying to identify genes differentially expressed in leukemia, a suspected hematopoietic stem cell disease. A human pre-leukemia model system, established by Dr. Jim Mulloy (Division of Experimental Hematology), is used for comparative analysis with publicly available human leukemia expression data. The model involves the transduction of primary human HS/PC with retroviral vectors expressing fusion gene transcripts found in certain subtypes of leukemia. The aim is to identify early genetic events in the development of leukemia using statistical analysis and supervised and unsupervised machine learning algorithms. The same methodologies can also be applied to study transcriptional deregulation caused by differential micro-RNA expression in neuroblastoma patients to identify molecular signatures specific for this neoplasm and to stratify these patients into risk groups. These studies are carried out in collaboration with Dr. Stella Davies (Division of Hematology/ Oncology) and Dr. C. Croce (Ohio State University, Columbus, Ohio).
Furthermore, we are planning to improve the molecular diagnostics for Fanconi Anemia (FA) patients. This rare, inherited, fatal, bone marrow failure disease involves at least 12 complementation groups and displays a highly variable clinical phenotype. The exact mechanism of this defect inof the hematopoietic stem cell (HSC) compartment remains elusive to this point. Nevertheless, loss-of-function mutations in any of the 12 known genes will lead to FA. The number of genes involved, the phenotypical heterogeneity, and the mostly private nature of mutations in these patients presents a considerable challenge for the molecular diagnosis of FA. Furthermore, other genetic diseases such as Nijmegen Breakage Syndrome and Bloom's Syndrome show overlap in clinical phenotype with FA. To systematically identify causative sequence mutations at the FA loci, provide accurate diagnosis of FA in patients and, as a long term goal, to eventually predict/assess the risk of the individual patient to develop BMF bone marrow failure and cancer, we are developing comprehensive mutation profiling by DNA sequence analysis involving the design of a high-density DNA microarray (SeqChip). The custom FA diagnostic gene chip will allow for rapid and accurate mutation identification of FA patients. The development of the FA diagnostic chip is done in collaboration with the Division of Human Genetics (Drs. Greg Grabowski, Richard Wenstrup and Kejian Zhang) and the Division of Pediatrics Informatics (Dr. Bruce Aronow).
For further information regarding Dr. Jansen's research, please contact Dr. Michael Jansen at 513-636-7930. For additional information about the Division of Experimental Hematology, please contact Dr. David Williams at 513-636-0364. The Division of Experimental Hematology can be found in Room 6529 of Location R (Research Foundation Building).
