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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Gkourogianni, Alexandra; Lodish, Maya B; Zilbermint, Mihail et al. (2015) Death in pediatric Cushing syndrome is uncommon but still occurs. Eur J Pediatr 174:501-7
Dagalakis, Urania; Lodish, Maya; Dombi, Eva et al. (2014) Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I. J Pediatr 164:620-4
London, Edra; Rothenbuhler, Anya; Lodish, Maya et al. (2014) Differences in adiposity in Cushing syndrome caused by PRKAR1A mutations: clues for the role of cyclic AMP signaling in obesity and diagnostic implications. J Clin Endocrinol Metab 99:E303-10
Basso, F; Rocchetti, F; Rodriguez, S et al. (2014) Comparison of the Effects of PRKAR1A and PRKAR2B Depletion on Signaling Pathways, Cell Growth, and Cell Cycle Control of Adrenocortical Cells. Horm Metab Res :
Beuschlein, Felix; Fassnacht, Martin; Assie, Guillaume et al. (2014) Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med 370:1019-28
Guillaud Bataille, M; Rhayem, Y; Sousa, S B et al. (2014) Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion. Eur J Endocrinol 170:151-60
Forlino, Antonella; Vetro, Annalisa; Garavelli, Livia et al. (2014) PRKACB and Carney complex. N Engl J Med 370:1065-7
Faucz, Fabio R; Zilbermint, Mihail; Lodish, Maya B et al. (2014) Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation. J Clin Endocrinol Metab 99:E1113-9
London, Edra; Nesterova, Maria; Sinaii, Ninet et al. (2014) Differentially regulated protein kinase A (PKA) activity in adipose tissue and liver is associated with resistance to diet-induced obesity and glucose intolerance in mice that lack PKA regulatory subunit type-II* Endocrinology :en20141122
Gourgari, Evgenia; Lodish, Maya; Keil, Meg et al. (2014) Post-operative growth is different in various forms of pediatric Cushing's syndrome. Endocr Relat Cancer 21:L27-31

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