Dr Siew Chai - Researcher Profile

Siew Chai

Address

Department of Physiology
Faculty of Medicine, Nursing & Health Sciences, Clayton

Biography

The memory mystery

Dr Siew Yeen Chai has learned over her 20-year research career to be cautious in discussing the potential applications of her work. However, she cannot hide her excitement when she talks about her recent research which may have important implications in understanding the causes and treatment of Alzheimer’s disease.

Siew has a personal connection to her research into neurodegenerative diseases as a number of her family and friends have suffered from these debilitating conditions.  While she did not choose her research path in response to her family's experiences,  she admits the search for the causes, as well as effective treatments, remains close to her heart, especially for the most common of the neurodegenerative diseases, Alzheimer's dementia.

Unfortunately, Siew's family experience is not uncommon.  As the population of countries such as Australia grow steadily older, the incidence of neurodegenerative diseases closely linked with ageing will increase.

Siew's research focuses on an enzyme identified in the brain by her lab, insulin-regulated aminopeptidase (IRAP). Siew and her colleagues found that blocking the activity of this enzyme in the brain results in improved performance in memory tasks.  

While working at the Howard Florey Institute prior to joining Monash University, Siew’s team, together with collaborator Professor Michael Parker of St Vincent’s Institute, began using a computer-based drug screening strategy to identify compounds that would act as an IRAP inhibitor. Using these in silico methods they were able to effectively and accurately sort through 1.5 million compounds to find ones with predicted high affinity for IRAP, which they were then able to develop into drug-like IRAP inhibitors. When introduced to normal rodents, these IRAP inhibitors improved performance in memory tasks. What was not expected was that when these newly discovered IRAP inhibitors were administered into Alzheimer's mouse models, they not only reversed memory loss, but actually showed signs of stopping the deposits of amyloid plaques, the pathological hallmarks of Alzheimer’s disease, in the brain. 

IRAP plays a role in muscle and fat cells, enabling glucose to be taken up in response to insulin. Quite what its role is in the brain, and the specific link between blocking its activity there and improved memory performance as well as the development of Alzheimer’s disease, is still unclear. This is the focus of Siew's current research endeavours.

For Siew, with her acute awareness of the debilitating effects of Alzheimer's, the recent findings from her lab have provided the highlight of her research career to date. 

"When we first stumbled on this discovery I thought, yes, this is meant to be," she says.

What has really interested the scientific community as well as the pharmaceutical and biotech industries are the indications that blocking IRAP activity might not only reverse memory loss, but also stop the progression of Alzheimer’s disease.  Siew has received a grant from Commercialisation Australia to work in partnership with Biolink to attract a pharmaceutical partner for her research.

"Now we are working on development of a second class of compounds that demonstrate the same effect as well as discovering the mechanism of the drug’s action so that we have confidence that blocking IRAP activity has the desired effect of stopping the progression of Alzheimer’s disease," Siew says.

Siew's work has led to the publication of 128 research papers and book chapters, and she has been awarded seven patents.

 

Qualifications

PHD MEDICINE
Institution: University of Melbourne
Year awarded: 1988
BACHELOR OF SCIENCE (HONOURS)
Institution: Monash University
Year awarded: 1983

Publications

Book Chapters

Albiston, A.L., Burns, P., Yeatman, H.R., Ng, L., Chai, S.Y., 2009, Is circulating insulin-regulated aminopeptidase (oxytocinase) during pregnancy restricted to humans?, in Handbook of Oxytocin Research: Synthesis, storage and release, actions and drug forms, eds H Jastrow & D Feuerbach, Nova Publishers Inc, USA, pp. 275-279.

Allen, A., O'Callaghan, E., Mendelsohn, F., Chai, S., 2009, Neuronal Angiotensin, in Encyclopedia of Neuroscience, eds LR Squire, Academic Press Elsevier Ltd, UK, pp. 697-702.

Jenkins, T., Mendelsohn, F., Albiston, A., Chai, S., 2007, Angiotensin IV binding site: The AT4 receptor or insulin-regulated aminopeptidass, in Hypertension and Hormone Mechanisms, eds RM Carey & DA Harrison III, Humana Press, USA, pp. 61-74.

Journal Articles

Pham, V., Albiston, A., Downes, C., Wong, C., Diwakarla, L.P., Ng, L., Lee, S., Crack, P., Chai, S., 2012, Insulin-regulated aminopeptidase deficiency provides protection against ischemic stroke in mice, Journal of Neurotrauma [P], vol 29, issue 6, Mary Ann Liebert, Inc. Publishers, USA, pp. 1243-1248.

Loyens, E., Schallier, A., Chai, S., De Bundel, D., Vanderheyden, P., Michotte, Y., Smolders, I., 2011, Deletion of insulin-regulated aminopeptidase in mice decreases susceptibility to pentylenetetrazol-induced generalized seizures, Seizure : the journal of the British Epilepsy Association [P], vol 20, issue 8, Elsevier Ltd, UK, pp. 602-605.

Albiston, A.L., Yeatman, H.R., Pham, V., Fuller, S.J., Diwakarla, S., Fernando, R.N., Chai, S.Y., 2011, Distinct distribution of GLUT4 and insulin regulated aminopeptidase in the mouse kidney, Regulatory Peptides [P], vol 166, issue 1-3, Elsevier BV, The Netherlands, pp. 83-89.

Morgan, B.J., Chai, S.Y., Albiston, A., 2011, GLUT4 Associated Proteins as Therapeutic Targets for Diabetes, Recent Patents on Endocrine, Metabolic and Immune Drug Discovery [P], vol 5, issue 1, Bentham Science Publications Ltd, The Netherlands, pp. 25-32.

Albiston, A., Diwakarla, S., Fernando, R., Mountford, S., Yeatman, H., Morgan, B., Pham, V., Holien, J., Parker, M., Thompson, P., Chai, S., 2011, Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers, British Journal of Pharmacology [P], vol 164, issue 1, John Wiley & Sons Ltd, UK, pp. 37-47.

Yang, R., Smolders, I., Vanderheyden, P., Demaegdt, H., Van Eeckhaut, A., Vauquelin, G., Lukaszuk, A., Tourwe, D., Chai, S., Albiston, A., Nahmias, C., Walther, T., Dupont, A., 2011, Pressor and renal hemodynamic effects of the novel angiotensin A peptide are angiotensin II type 1A receptor dependent, Hypertension [P], vol 57, issue 5, Lippincott Williams & Wilkins, USA, pp. 956-964.

Ascher, D., Cromer, B., Morton, C., Volitakis, I., Cherny, R., Albiston, A., Chai, S., Parker, M., 2011, Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain, Biochemistry [P], vol 50, issue 13, American Chemical Society, USA, pp. 2611-2622.

Albiston, A.L., Fernando, R.N., Yeatman, H.R., Burns, P., Ng, L., Daswani, D., Diwakarla, S., Pham, V., Chai, S.Y., 2010, Gene knockout of insulin-regulated aminopeptidase: Loss of the specific binding site for angiotensin IV and age-related deficit in spatial memory, Neurobiology Of Learning And Memory [P], vol 93, issue 1, Academic Press, USA, pp. 19-30.

Albiston, A., Pham, V., Ye, S., Ng, L., Lew, R., Thompson, P., Butler, J., Morton, C., Parker, M., Chai, S., 2010, Phenylalanine-544 plays a key role in substrate and inhibitor binding by providing a hydrophobic packing point at the active site of insulin-regulated aminopeptidase, Molecular Pharmacology [P], vol 78, issue 4, The American Society for Pharmacology and Experimental Therapeutics, Bethesda Maryland USA, pp. 600-607.

Yang, R., Walther, T., Gembardt, F., Smolders, I., Vanderheyden, P., Albiston, A., Chai, S., Dupont, A., 2010, Renal vasoconstrictor and pressor responses to angiotensin IV in mice are AT1a-receptor mediated, Journal of Hypertension [P], vol 28, issue 3, Lippincott Williams & Wilkins, USA, pp. 487-494.

De Bundel, D., Smolders, I., Yang, R., Albiston, A., Michotte, Y., Chai, S., 2009, Angiotensin IV and LVV-haemorphin 7 enhance spatial working memory in rats: effects on hippocampal glucose levels and blood flow, Neurobiology Of Learning And Memory [P], vol 92, issue 1, Academic Press Inc Elsevier Science, USA, pp. 19-26.

Segura, E., Albiston, A., Wicks, I., Chai, S., Villadangos, J., 2009, Different cross-presentation pathways in steady-state and inflammatory dendritic cells, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 106, issue 48, National Academy of Sciences, USA, pp. 20377-20381.

Pham, V., Burns, P., Albiston, A.L., Yeatman, H.R., Ng, L., Diwakarla, L.P., Chai, S.Y., 2009, Reproduction and maternal behavior in insulin-regulated aminopeptidase (IRAP) knockout mice, Peptides [P], vol 30, issue 10, Elsevier Inc., USA, pp. 1861-1865.

Vinh, A., Widdop, R.E., Chai, S.Y., Gaspari, T.A., 2008, Angiotensin IV-evoked vasoprotection is conserved in advanced atheroma, Atherosclerosis, vol 200, issue 1, Elsevier Ireland Ltd, Ireland, pp. 37-44.

Cohen, M., Wuillemin, C., Chai, S., Bischof, P., 2008, Effects of ligands or substrate of insulin-regulated aminopeptidase (IRAP) on trophoblast invasion, Journal Of Peptide Science [P], vol 14, issue 7, Wiley-Blackwell, USA, pp. 883-887.

Albiston, A.L., Morton, C.J., Ng, H.L., Pham, V., Yeatman, H.R., Ye, S., Fernando, R.N., De Bundel, D., Ascher, D.B., Mendelsohn, F.A., Parker, M.W., Chai, S.Y., 2008, Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase, Faseb Journal [P], vol 22, issue 12, Federation of American Societies for Experimental Biology, USA, pp. 4209-4217.

Ye, S., Chai, S.Y., Lew, R.A., Ascher, D.B., Morton, C.J., Parker, M.W., Albiston, A.L., 2008, Identification of modulating residues defining the catalytic cleft of insulin-regulated aminopeptidase, Biochemistry and Cell Biology, vol 86, issue 3, NRC Research Press, Canada, pp. 251-261.

Frnando, R., Albiston, A., Chai, S., 2008, The insulin-regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus - Potential role in modulation of glucose uptake in neurones?, European Journal Of Neuroscience [P], vol 28, issue 3, Wiley-Blackwell, USA, pp. 588-598.

Jenkins, T., Chai, S., 2007, Effect of chronic angiotensin converting enzyme inhibition on spatial memory and anxiety-like behaviours in rats, Neurobiology Of Learning And Memory [P], vol 87, issue 2, Academic Press Inc Elsevier Science, USA, pp. 218-224.

Ye, S., Chai, S.Y., Lew, R.A., Albiston, A.L., 2007, Insulin-regulated aminopeptidase: analysis of peptide substrate and inhibitor binding to the catalytic domain, Biological Chemistry, vol 388, issue 4, Walter de Gruyter & Co, Berlin Germany, pp. 399-403.

Fernando, R.N., Luff, S.E., Albiston, A.L., Chai, S.Y., 2007, Sub-cellular localization of insulin-regulated membrane aminopeptidase, IRAP to vesicles in neurons, Journal of Neurochemistry, vol 102, issue 3, Blackwell Publishing, Oxford England UK, pp. 967-976.

Albiston, A., Peck, G., Yeatman, H., Frnando, R., Ye, S., Chai, S., 2007, Therapeutic targeting of insulin-regulated aminopeptidase: heads and tails?, Pharmacology and Therapeutics [P], vol 116, issue 3, Pergamon-Elsevier Science Ltd, UK, pp. 417-427.

Peck, G.R., Ye, S., Pham, V., Fernando, N.R., Macaulay, S.L., Chai, S.Y., Albiston, A.L., 2006, Interaction of the Akt substrate, AS160, with the glucose transporter 4 vesicle marker protein, insulin-regulated aminopeptidase, Molecular Endocrinology [P], vol 20, issue 10, The Endocrine Society, USA, pp. 2576-2583.

Paxinos, G., Chai, S.Y., Christopoulos, G., Huang, X., Toga, A.W., Wang, H.Q., Sexton, P.M., 2004, In vitro autoradiographic localization of calcitonin and amylin binding sites in monkey brain, Journal of Chemical Neuroanatomy, vol 27, issue 4, Elsevier Science BV, The Netherlands, pp. 217-236.

Lew, R.A., Mustafa, T., Ye, S., McDowall, S.G., Chai, S.Y., Albiston, A.L., 2003, Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP), Journal of Neurochemistry, vol 86, issue 2, Blackwell Publishing, Oxford UK, pp. 344-350.

Lee, J., Mustafa, T., McDowall, S.G., Mendelsohn, F.A., Brennan, M., Lew, R.A., Albiston, A.L., Chai, S.Y., 2003, Structure-activity study of LVV-Hemorphin-7: angiotensin AT4 receptor ligand and inhibitor of insulin-regulated aminopeptidase, Journal of Pharmacology and Experimental Therapeutics, vol 305, issue 1, American Society for Pharmacology and Experimental Therapeutics, Bethesda USA, pp. 205-211.

McKinley, M.J., Albiston, A.L., Allen, A.M., Mathai, M.L., May, C.N., McAllen, R.M., Oldfield, B.J., Mendelsohn, F.A., Chai, S.Y., 2003, The brain renin-angiotensin system: location and physiological roles, International Journal of Biochemistry and Cell Biology [P], vol 35, issue 6, Pergamon, UK, pp. 901-918.

Reardon, K.A., Chai, S.Y., Mendelsohn, F.A.O., Horne, M.K., 2000, The angiotensin converting enzyme (ACE) inhibitor, perindopril, modifies the clinical features of Parkinson's disease, Australian New Zealand Journal of Medicine, vol 30, Adis Press Australasia Pty Ltd, Balgawlah Australia, pp. 48-53.

Conference Proceedings

Chai, S.Y., Yeatman, H.R., Parker, M.W., Ascher, D.B., Thompson, P., Mulvey, H.T., Albiston, A.L., 2008, Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase, 8th International Conference on Alzheimer's Disease Drug Discovery, 15-16 Oct 2007, BioMed Central, USA, p. 0.

Postgraduate Research Supervisions

Current Supervision

Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Inhibition of an Aminopeptidase: A Novel Therapeutic Stratergy For Stroke.
Supervisors:
Chai, S (Main), Pham, V (Associate).