The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands (especially the pituitary gland and to a lesser extent the thyroid gland). We have studied congenital adrenal hypoplasia caused by triple A syndrome and other defects, other multiple endocrine deficiencies, familial hyperaldosteronism, adrenocortical and thyroid cancer, pituitary tumors and multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid and adrenal glands, and Carney complex (CNC), an autosomal dominant disease. CNC is a MEN syndrome affecting the pituitary, adrenal cortex, thyroid, and the gonads, and is associated with a variety of other tumors, including myxomas and schwannomas, and skin pigmentation defects (lentigines, cafe-au-lait spots, and nevi). We have identified the regulatory subunit type 1-A of protein kinase A (PKA), which is coded by the PRKAR1A gene as the gene responsible for most CNC patients. Thus, a significant part of our work is now focused on PKA-stimulated signaling pathways, PKA effects on tumor suppression and/or development, the cell cycle and chromosomal stability. Prkar1a-specific animal models have also been created to address the tumor-promoting effects of this gene and serve as models for possible therapies. In addition, genes that are mutated in patients with CNC-like and other froms of inherited adrenal tumors are being investigated. Most recently, mutations in a phosphodiesterase genes - phosphodiesterase 11A (PDE11A) and PDE8B - were identified in patients with bilateral adrenocortical hyperplasia. A mouse model of PDE11A deficiency is being studied, and mutations of this gene are being sought in other endocrine tumors. We also started the effort to generate a mouse model for PDE8B. Most recently, we have elucidated the causative genetic defects in Carney-Stratakis syndrome (CSS) and we have embarked on a new search for genes that are related to tumors that develop in association with CSS and a similar condition (Carney Triad).

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Toledo, Rodrigo A; Sekiya, Tomoko; Horvath, Anelia et al. (2012) Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2. Clin Endocrinol (Oxf) 76:147-8
Briassoulis, George; Quezado, Martha; Lee, Chyi-Chia Richard et al. (2012) Myxoma of the ear lobe in a 23-month-old girl with Carney complex. J Cutan Pathol 39:68-71
Tomic, Melanija; Kucka, Marek; Kretschmannova, Karla et al. (2011) Role of nonselective cation channels in spontaneous and protein kinase A-stimulated calcium signaling in pituitary cells. Am J Physiol Endocrinol Metab 301:E370-9
Almeida, Madson Q; Harran, Michelle; Bimpaki, Eirini I et al. (2011) Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. J Clin Endocrinol Metab 96:E728-38
Janeway, Katherine A; Kim, Su Young; Lodish, Maya et al. (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108:314-8
Farrell, William E; Azevedo, Monalisa F; Batista, Dalia L et al. (2011) Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma. J Clin Endocrinol Metab 96:E1905-14
Zacharin, Margaret; Bajpai, Anurag; Chow, Chung Wo et al. (2011) Gastrointestinal polyps in McCune Albright syndrome. J Med Genet 48:458-61
Faucz, Fabio Rueda; Horvath, Anelia; Rothenbuhler, Anya et al. (2011) Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer. J Clin Endocrinol Metab 96:E135-40
Song, Woo-Jin; Seshadri, Madhav; Ashraf, Uzair et al. (2011) Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metab 13:308-19
King, Kathryn S; Chen, Clara C; Alexopoulos, Dimitrios K et al. (2011) Functional imaging of SDHx-related head and neck paragangliomas: comparison of 18F-fluorodihydroxyphenylalanine, 18F-fluorodopamine, 18F-fluoro-2-deoxy-D-glucose PET, 123I-metaiodobenzylguanidine scintigraphy, and 111In-pentetreotide scintigraphy. J Clin Endocrinol Metab 96:2779-85

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