NHRF IBRB MOLECULAR ENDOCRINOLOGY PROGRAM

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Program Staff
Permanent Dr M. N. Alexis Researcher A,
Head Prof C. E. Sekeris IBRB director I.
Florentin Technician Z. Ganidou Lab
assistant A. Nastou Lab assistant Externally
funded D. Siriani Post Doc
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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Research Aims

• To study the mechanism of action of the
  glucocorticoid receptor at the subcellular,
  cellular and organism levels.
• To elaborate on the prognostic and predictive
  significance of estrogen receptor in breast
  cancer and to develop tissue- specific
  anti-estrogens to combat the disease.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Research Lines

• Glucocorticoid receptor (GR) function in stressed
  cells.
• GR ontogeny in the brain and effects of stress on
  cognitive performance.
• Classical and non-classical steroid hormone
  receptors (SHRs) in unconventional roles.
• Development of anti-estrogens for the
  reproductive system that mimic the action of
  estrogens in peripheral systems.
• Molecular mechanisms of action of tissue-specific
  anti-estrogens and of selected phytoestrogens and
  xenoestrogens.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Research Achievements

• GR function in thermally and metabolically
  stressed cells.
• We analysed the subunit composition of GR
  complexes with heat shock proteins (HSPs) and
  have shown that HSP70 is the limiting determinant
  of receptor function in heat-shocked cells and
  that maintenance of GR function, in conjunction
  with thermal stabilization of CAT mRNA, amplifies
  hormonal induction of CAT expression following
  heat shock of heat-conditioned cells.
• We have also shown that while in quiescent rat
  liver glucocorticoids (GCs) are required to
  increase the efficiency of nuclear processing of
  the tyrosine aminotransferase primary transcript,
  in liver that is regenerating after 70
  hepatectomy the efficiency of this processing
  increases in the absence of GCs, suggestive of
  emergency measures taken to maintain matabolic
  homeostasis.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Research Achievements

• Brain GR ontogeny and cognitive effects of
  stress.
• We have shown that stress differentially affects
  spatial learning and memory, depending on the
  gender of the rat and that GR is expressed in
  rat brain as early as day 13 of gestation. We
  have postulated a developmentally regulated
  molecular basis to underlie gender differences in
  cognitive performance.
• Classical and non-classical receptors in
  unconventional roles.
• We have shown that classical GR relocates to
  mitochondria in the presence of GCs and have
  proposed a direct regulation of mitochondrial
  gene expression by GR. We have also shown that
  non-classical testosterone receptors in the
  plasma membrane of T cells mediate the
  immune-suppressive effects of the hormone by
  extracellular Ca2 influx.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Research Achievements

• Development of tissue-specific anti-estrogens.
• Using estrogen receptor a and ß subtypes in vitro
  and ex-vivo in different cell and promoter
  contexts, as well as rodent bio-assays we screen
  non-uterotrophic raloxifene analogues synthesized
  by IOPC researchers for their ability to prevent
  osteoporosis and hypercholesterolemia in the OVX
  rat.
• Mechanisms of action of phytoestrogens and
  xenoestrogens.
• We found that coumestrol is highly estrogenic by
  several in vitro and ex-vivo assays.
  Up-regulation of detoxifying enzymes by
  phytoestrogens but not by estradiol may underlie
  their anticancer activity. We also found that
  alkyl-phenols are marginally estrogenic.
  Interference with the signaling of the
  non-classical estrogen receptor may underlie
  their adverse reproductive effects.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Refereed Papers PhD Theses

• 9 Publications
• 252 Citations
• 5 Ph.D Theses
• Baki A., now at the Dept. of Psychiatry, Mount
  Sinai School of Medicine, New York.
• Demonacos C., Dept. of Biochemistry and Molecular
  Biology, Univ. of Glasgow.
• Georgakopoulos A., Dept. of Psychiatry, Mount
  Sinai School of Medicine, New York.
• Karagianni N., till recently at the Unite INSERM
  373, Institute Necker, Paris.
• Mitsiou D.J., now at the Dept. of Molecular
  Biology, University of Nijmegen.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
External funding, collaborations, relations with
industry

• Coordination of 3 externally funded projects
  Total NHRF budget 146.270.000 GRD. Program
  share 85.070.000 GRD.
• Collaboration with 8 University/Research Center
  groups.
• Relations with a Pharmaceutical Company a
  Diagnostic Center.

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NHRF - IBRB - MOLECULAR ENDOCRINOLOGY PROGRAM
Perspectives

• Decipher the role of ER? and ER? in breast cancer
  progression to antiestrogen resistance and
  develop raloxifene and chemosensitizing
  dexamethasone analogues for the treatment of
  breast cancer and leukemia.
• Elaborate on the prognostic and predictive
  significance of ER?1, ER?2, c-erbB2, and PTHrP
  for breast cancer Towards a patient-individualize
  d therapy that limits morbidity associated with
  the disease.
• Examine the cognitive performance of aged female
  rats exposed to phytoestrogen replacement
  therapies and to antiestrogens that could be
  prescribed for long-term use to prevent breast
  cancer in high-risk women.
• Investigate the physiological role of the beta
  isoform of GR, a non-hormone-binding entity
  generated by alternative splicing in a wide
  variety of cells and tissues.