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Dr. Stratakis in the lab The goal of the Section on Genetics and Endocrinology's (SEGEN) work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands (i.e. the pituitary gland) and tissues of neuroectodermal origin (i.e. the melanocytes).

Our laboratory has studied families with Carney complex (CC) (also known as the "complex of myxomas, spotty skin pigmentation, endocrine overactivity and schwannomas") and related syndromes.

The long-term goal of our laboratory is to elucidate the molecular defects leading to disorders of the pituitary and adrenal glands, especially those associated with multiple tumors and abnormalities in other endocrine glands, to develop better therapies for our patients and generate knowledge that could be applicable on other, common conditions. In the last years, the positional cloning of the PRKAR1A gene, which is responsible for adrenocortical hyperplasia or Carney complex (CNC) in a subset of patients, represents a successful application of the paradigm of a rare disorder that was used to identify a gene with novel and wide functions. This discovery led to the more recent identification of PRKACA, PRKACB and the related PDE11A and PDE8B genes, all involved in one or the other phenotype of endocrine tumors, mostly adrenal and pituitary tumors.

Since all these genes participate in the cAMP/PKA signaling pathway, our short-term main goals relate to the elucidation of this pathway's role in endocrine and non-endocrine tumorigenesis by studying in vitro and in vivo its interactions with other molecular partners and signaling pathways and the phenotypic effects of its genetic (and possible epigenetic) alterations.

Secondary goals of this project include the continuation of the efforts, and in some cases, collaborative investigations, to identify other endocrine tumor-causing genes. Along these lines, recently we have elucidated the molecular defects in Carney-Stratakis syndrome and we are looking for the genes in Carney Triad and related conditions.

Laboratory-based projects include:

  1. Characterization of Prakar1a-, Pde11a-, Pde8b-, Prkaca- and Prkacab-specific animal models.
  2. Elucidation of the role of PRKAR1A, PRKACA, PRKACB and the PDE11A and PDE8B and their molecular partners on proliferation, cell cycle, apoptosis and growth. We are using (1) human cell lines established from CNC patients and/or their tumors carrying mutations; (2) mouse embryonic fibroblasts (MEF) established from mouse embryos; and (3) standard, commercially available human and mouse cell lines transfected with mutant genes and other constructs, as well as and synthetic short-interfering RNA oligonucleotides (siRNAs) to answer basic questions: Do shifts in PKA activity affect cell proliferation, apoptosis or morphology? What are the corresponding changes in the cell cycle and the likely molecular partners or signaling pathways?
  3. Cloning of other genes responsible for CNC, PPNAD and related disorders. We continue our efforts to identify other genetic defects causing ACTs, in some instances on a collaborative basis. Genome wide-screens and other tools (e.g comparative genomic hybridization, next generation (next-GEN) sequencing) are applied in families and tumors. Tumor microarray analysis and "deep" (next-GEN) sequencing provide important information for new genetic defects and downstream pathways responsible for tumorigenesis.
  4. Phenotypic characterization of CNC, PPNAD and patients with other endocirne tumors and genotype correlation; these studies are being done at the NIH Clinical Center.

Dr. Stratakis also the Program Director for Pediatric Endocrinology at the NIH and a member of the Medical Advisory Board for the Cushing's Support and Research Foundation.

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