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
Almeida, Madson Q; Tsang, Kit Man; Cheadle, Chris et al. (2011) Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. Hum Mol Genet 20:165-75
Briassoulis, George; Damjanovic, Svetozar; Xekouki, Paraskevi et al. (2011) The glucocorticoid receptor and its expression in the anterior pituitary and the adrenal cortex: a source of variation in hypothalamic-pituitary-adrenal axis function; implications for pituitary and adrenal tumors. Endocr Pract 17:941-8
Raygada, Margarita; Pasini, Barbara; Stratakis, Constantine A (2011) Hereditary paragangliomas. Adv Otorhinolaryngol 70:99-106
Gaujoux, Sebastien; Tissier, Frederique; Ragazzon, Bruno et al. (2011) Pancreatic ductal and acinar cell neoplasms in Carney complex: a possible new association. J Clin Endocrinol Metab 96:E1888-95
Moraitis, Andreas; Stratakis, Constantine (2011) Adrenocortical causes of hypertension. Int J Hypertens 2011:624691
Carney, J Aidan; Young, William F; Stratakis, Constantine A (2011) Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome. Am J Surg Pathol 35:1311-26
Lindsay, John R; Oldfield, Edward H; Stratakis, Constantine A et al. (2011) The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing's disease after transsphenoidal surgery. J Clin Endocrinol Metab 96:2057-64
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

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