Dr Giavanna Angeli
The major focus of my research has been the intracellular signalling mechanisms, with a particular emphasis on protein kinases and protein phosphorylation. My PhD studies explored signalling through cAMP-dependent protein kinase (PKA) in the pituitary. Corticotropin-releasing hormone is a peptide hormone released from the hypothalamus during periods of stress and also plays an important role in depression, maturation of fetal lungs and in pregnancy where it is thought to be a key player in the onset of labour in humans.
Since the early 1980s CRH has been known activate PKA in mouse and rat pituitary, but the steps following PKA activation had never been studied in great detail. My work has addressed this lack of knowledge and revealed that CRH does not just simply activate PKA to phosphorylate protein substrates but rather that the PKA activation sets into play a complicated sequence of events involving both the PKA enzyme itself and other protein kinase cascades.
My major findings are summarised as follows:>
- The phosphorylation of some proteins changed in response to CRH and AVP treatment.
- These proteins appear to be phosphorylated by a protein kinase activated subsequent to PKA activation, most probably a MAP kinase like activity.
- Changing cAMP levels impacts on the autophosphorylation of the regulatory subunit (type II) of PKA. I have studied this autophosphorylation reaction in great detail and have proposed a model for the role of changing cAMP levels and autophosphorylation of the regulatory subunit in the pituitary.
- The different isoforms of the regulatory subunit have different sensitivities to cAMP and different autophosphorylation rates.
- I have demonstrated dramatic effects of CRH and AVP on protein levels of cAMP-dependent protein kinase C subunit in AtT20 cells, suggesting PKA catalytic subunit levels are controlled by rapid degradation or down regulation when both cAMP and protein kinase C pathways are activated.
Over the last three years I have also developed an interest in apoptosis and its roles in the vascular tissues. Firstly I studied the connection between nitric oxide and apoptosis in human umbilical vein endothelial cells. High doses of nitric oxide promote apoptosis while low doses confer protection on endothelial cells. I demonstrated a loss of Protein Kinase G protein at higher levels of nitric oxide suggesting a link between PKG and the protective pathway. Intimal hyperplasia is a major factor leading to restenosis following vascular grafting. More recently I have been involved in studies investigating the role of apoptosis of vascular smooth muscle cells in the inhibition of intimal hyperplasia following vascular grafting.
Currently I am working with Dr Rick Nicholson's team where Kristy Shipman and I are looking at the signalling aspects of CRH gene expression. I am using proteomic approaches, in collaboration with Dr Phil Robinson from the Cell Signalling Unit at the Children's Medical Research Institute at Westmead to identify proteins which bind to a novel transcription factor which functions through the cAMP-response element of the CRH gene. I am also investigating the phosphorylation of this novel transcription factor.
I am also the Ethics Officer for the Mothers and Babies Research centre where I coordinate human and animal ethics for all of the centres' research projects.
Non-refereed Journal Articles
Pei Huang, Wayne J Hawthorne, Ao Peng, Giavanna L Angeli, Heather J Medbury and John P Fletcher (2001). Calcium channel antagonist verapamil inhibits neointimal and enhances apoptosis in a vascular graft model. The American Journal of Surgery 181, 492-498.
Pei Huang, Wayne J Hawthorne, Ao Peng, Giavanna L Angeli, Heather J Medbury and John P Fletcher (2002). Perigraft adventitia and intima remodelling following synthetic patch graft in sheep carotid artery: role of apoptosis and proliferation. Journal of Vascular Surgery (Manuscript #2010260).
The following manuscripts are currently being finalised for submission:
Giavanna L Angeli, Roger Smith and Phillip J Robinson (2002). Isoform differences in the intramolecular autophosphorylation reaction of the regulatory subunit (type II) of cAMP-dependent protein kinase. To be submitted to Molecular and Cellular Endocrinology.
Giavanna L Angeli, Jenny Rusak, Maria Bowman, Roger Smith and Phillip J Robinson (2002). Stable activation, degradation and increased translation of the catalytic subunit of cAMP-dependent protein kinase in AtT20 cells. In preparation.
Giavanna L. Smith, He Li, Roger Smith and Phillip J Robinson. A novel sensitive assay for measuring activation of cAMP-dependent protein kinase in ovine pituitary cells. 37th Annual Scientific Meeting, The endocrine Society of Australia Proceedings September 1994, Brisbane Australia.
Giavanna L. Smith, He Li, Xin Wang, Roger Smith and Philip J. Robinson. Activation and substrates of cAMP-dependent protein kinase in ovine pituitary cells. FASEB Summer Conference on Protein Kinases and Protein Phosphorylation, July 1995, Copper Mountain, Colorado, USA.
Giavanna L. Smith, He Li, Xin Wang, Roger Smith and Phillip J Robinson. CRH activates cAMP-dependent protein kinase and stimulates protein phosphorylation in ovine anterior pituitary cells. ANZAAS Congress, September 1995, Newcastle, Australia.
Giavanna L. Smith, Xin Wang, Roger Smith and Phillip J Robinson. Intramolecular autophosphorylation of the regulatory subunit of cAMP-dependent protein kinase in ovine anterior pituitary. 10th International Congress of Endocrinology. San Francisco, June 1996.
Giavanna L. Smith, Xin Wang, Roger Smith and Phillip J Robinson. Intramolecular autophosphorylation of the regulatory subunit of cAMP-dependent protein kinase in ovine anterior pituitary. The Endocrine Society of Australia Proceedings, Sydney, September 1996.
Giavanna L. Smith, Jenny Rusak, Xin Wang, Roger Smith and Phillip J Robinson. Stable activation, degradation and increased translation of the regulatory subunit of cAMP-dependent protein kinase in AtT20 pituitary cells. 41st Annual Conference for the Australian Society for Biochemistry and Molecular Biology Incorporated. This abstract won the Best Student Poster Prize for this conference.
Giavanna L. Smith, Jenny Rusak, Xin Wang, Roger Smith and Phillip J Robinson. Intracellular signalling pathways involved in corticotropin releasing hormone action: stable activation, degradation and increased translation of the catalytic subunit of cAMP-dependent protein kinase. ASMR NSW Scientific Meeting, June 1998, Sydney Australia.
Membership of Societies and Professional Bodies
Australian Society for Biochemistry and Molecular Biology
Endocrine Society of Australia