description): Carney Complex (CNC) is an autosomal dominant tumor syndrome that is best classified as a novel form of multiple endocrine neoplasia. In this application, Dr. Lawrence S. Kirschner proposes to isolate the genetic defect causing CNC and to begin the functional study of the encoded protein product. In the first portion of this study, a positional cloning strategy will be undertaken to isolate the genetic lesion responsible for CNC. 24 families with CNC have been collected, and a candidate region on chromosome 2pl6 has been defined by genetic recombination analysis. A yeast and bacterial artificial chromosome (YAC and BAG, respectively)-based contig of this area will be constructed and utilized to map expressed sequences into the minimal candidate region. Those mRNA sequences falling in the candidate interval will be cloned and screened for mutations using denaturing high performance liquid chromatography (D-HPLC) analysis. Once the CNC gene is identified, this information will be used to generate transgenic mice lacking the CNC gene, and the effects of this mutation during fetal development, especially of the endocrine system, will be examined. At the same time, mutations in the CNC gene will be sought in CNC associated sporadic tumors, such as cardiac myxomas, benign and malignant adrenal tumors, and thyroid cancers. The long-term goal of this project is to identify the role that the CNC gene product plays in the normal development of the endocrine and other systems, as well as the role that the mutated gene plays in tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Career Transition Award (K22)
Project #
5K22HD001323-02
Application #
6725513
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Winer, Karen
Project Start
2003-03-21
Project End
2005-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
2
Fiscal Year
2004
Total Cost
$149,256
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kirschner, Lawrence S; Yin, Zhirong; Jones, Georgette N et al. (2009) Mouse models of altered protein kinase A signaling. Endocr Relat Cancer 16:773-93
Nadella, Kiran S; Saji, Motoyasu; Jacob, Naduparambil K et al. (2009) Regulation of actin function by protein kinase A-mediated phosphorylation of Limk1. EMBO Rep 10:599-605
Jones, Georgette N; Tep, Chhavy; Towns 2nd, William H et al. (2008) Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production. Neoplasia 10:1213-21
Nadella, Kiran S; Jones, Georgette N; Trimboli, Anthony et al. (2008) Targeted deletion of Prkar1a reveals a role for protein kinase A in mesenchymal-to-epithelial transition. Cancer Res 68:2671-7
Yin, Zhirong; Jones, Georgette N; Towns 2nd, William H et al. (2008) Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 117:1414-22
Pavel, Emilia; Nadella, Kiran; Towns 2nd, William H et al. (2008) Mutation of Prkar1a causes osteoblast neoplasia driven by dysregulation of protein kinase A. Mol Endocrinol 22:430-40
Kirschner, Lawrence S; Kusewitt, Donna F; Matyakhina, Ludmila et al. (2005) A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 65:4506-14
Nadella, Kiran S; Kirschner, Lawrence S (2005) Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res 65:10307-15