Lawrence S. Kirschner, MD, PhD
Associate Professor of Internal Medicine
Division of Endocrinology, Diabetes and Metabolism
Associate Professor, Human Cancer Genetics Program,
Arthur G. James Cancer Hospital and Solove Research Institute
Tzagournis Medical Research Facility
420 W 12th Ave
Columbus , OH 43210
Phone: (614) 292-1190
Fax: (614) 247-6842
Lawrence(dot)Kirschner(at)osumc(dot)edu

Research Interests
Dr. Kirschner’s research is aimed at understanding the molecular events leading to the formation of tumors of the endocrine glands, and the relationship of these processes to the differentiation of these tissues. Using human diseases characterized by tumor formation in multiple endocrine glands (multiple endocrine neoplasia, Types 1 and 2 and the Carney Complex) as a conceptual framework, the laboratory is developing genetically altered mouse models as a means to investigate the formation of tumors in the endocrine (and other) organs. These studies may ultimately lead to a better understanding of the fundamental differences between the growth and development of the endocrine glands in comparison to other tissues in the human body. .

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
Princeton University, Princeton, NJ .1986 A.B. in Chemistry

Albert Einstein College of Medicine, Bronx, NY. 1993 M.D.-Ph.D. in Molecular Pharmacology

1993-96 Internship and Residency in Internal Medicine, University of Minnesota, Minneapolis, MN

1996-99 Clinical Fellowship, Endocrinology and Metabolism, National Institutes of Health, Bethesda, MD

1999-2002 Senior Staff Fellow, Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, NICHD, NIH, Bethesda, MD

Recent Publications
Stratakis, C.A., Kirschner L.S. , Taymans S.E., Tomlinson I.P.M., Torpy D.J., Eccles D., Basson C.T., Carney J.A. (1998). Carney Complex, Peutz-Jeghers Syndrome, Cowden Disease, and Bannayan-Zonana Syndrome share cutaneous and endocrine manifestations but not genetic loci. J.Clin. Endocrinol. Metab. 83: 2972-2976.

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 C.A. (2000). Mutations of the gene encoding the protein kinase A type I-a regulatory subunit in patients with the Carney complex. Nature Genetics 21:89-92.

Stratakis, C.A., Kirschner, L.S., and Carney, J.A. (2001). Clinical and molecular features of the Carney Complex: Diagnostic criteria and recommendations for patient evaluation.J Clin Endocrinol Metab. 86:4041-6.

Kirschner L.S.,Sandrini, F., Monbo, J. Lin, J.P., Carney, J.A.,and Stratakis C.A. (2000). Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum. Mol. Genet.:3037-46.

Sandrini, F., Matyakhina, L., Sarlis, N.J., Kirschner, L.S., Farmakidis, C., Gimm, O., Stratakis, C.A. (2002) Regulatory subunit type I-a of protein kinase A (PRKAR1A): A tumor-suppressor gene for sporadic thyroid cancer. Genes, Chromosomes and Cancer, published online: 27 Jun 2002