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Lawrence S. Kirschner
Research Interests Specific projects currently underway in the laboratory include the following: Creation of an in vivo model for Carney Complex. Carney complex is an inherited tumor syndrome that consists of spotty skin pigmentation, myxoma tumors of the heart and other organs, pigmented schwannomas and tumors of the endocrine glands. The gene that causes this disease in approximately 40% of known cases was recently identified as PRKAR1A ( Type 1A regulatory subunit of Protein Kinase A), a key mediator of signaling in endocrine tissues. Because of the rarity of this disease and the limited availability of tumor specimens from patients, the creation of a mouse model will allow important investigations into the mechanism by which inactivation of this gene causes the tumorigenesis observed in patients. Additionally, the use of different inbred mouse strains may allow the determination of modifying genes that affect expression of the disease phenotype. The second portion of this project involves the tissue-specific inactivation of both alleles of PRKAR1A in endocrine tissues to examine the effect of complete loss of this gene product on normal organ development and tumor formation. These conditional KO mice have been generated, and are currently being observed for tumors. In vitro studies of the biochemistry of Carney Complex mutations The use of mouse embryonic fibroblasts and primary organ cultures from the PRKAR1A knockout mice provides an excellent in vitro system for studying the effect of loss of Prkar1a on the variety of signaling pathways involved in cell growth and differentiation. Furthermore, endocrine gland primary culture studies will allow the laboratory to probe the effects of loss of this gene on the specific signaling pathways that are responsible for hormone secretion by endocrine cells. Genetic interaction of endocrine tumor genes. Genes for most of the genetic syndromes that involve tumors of the endocrine system have been identified, but little is known about their interactions in vivo. Using transgenic mice as a model system, mice that lack one or both copies of different endocrine tumor genes (e.g., the gene for MEN1 or the gene for Peutz-Jeghers syndrome) will be mated with mice lacking other tumor genes to look at the genetic interaction and effects on tumor formation and growth. Similarly, genes that are known to play important roles in endocrine cancers (e.g., p53 in adrenal cancer) will be manipulated in concert with the endocrine tumor genes. Analysis of these tumors at the biochemical level and correlation with the genetic alterations should provide insights into the complex interactions of this set of proteins. Positional cloning of the second gene for Carney Complex. In collaboration with Dr. Constantine Stratakis at the National Institutes of Health, families in whom no mutations of PRKAR1A were detected will continue to be analyzed with the goal of identifying the second CNC disease gene. Genetic mapping of these families has already localized the candidate locus to a small region on the short arm of chromosome 2. Ongoing analysis of the data being generated by the Human genome project continues to provide new leads to potential candidate genes for screening. Once this gene is identified, a mouse model for the mutation will be created and analyzed in a fashion similar to that described above. Education & Training 1993-96 Internship and Residency in Internal Medicine, 1996-99 Clinical Fellowship, Endocrinology and Metabolism, National Institutes of Health, 1999-2002 Senior Staff Fellow, Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, NICHD, NIH, Recent Publications Kirschner L.S., Taymans S.E., Pack S., Pak E., Pike B.L., Chandrasekharappa S.C., Zhuang Z., Stratakis C.A. Constantine A. Stratakis. (1999). Genomic Mapping of Chromosomal Region 2p15-p21 (D2S378-D2S391): Integration of Genemap’98 within a Framework of Yeast and Bacterial Artificial Chromosomes Kirschner L.S., Carney, J.A., Pack, S., Taymans, S.E., Giatzakis, C.G., Cho, Y.S., Ho-Chung, Y.S., Stratakis Stratakis, Kirschner L.S.,Sandrini, F., Monbo, J. Lin, J.P., Carney, J.A.,and Stratakis Sandrini, F., Matyakhina, L., |
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