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Dr Siew Yeen Chai
NHMRC Senior Research Fellow
Senior Lecturer - Department of Physiology

Address
Department of Physiology
Monash University  VIC 3800
Australia

Located
Office: Room F247 Lab:13 , Building 13F (Physiology) at Clayton Campus

Tel: +61 3 990 52515
Fax: +61 3 990 52547
Email: Siew.Chai@monash.edu

Background

Dr Siew Yeen Chai completed her Bachelor of Science with honours degree at Monash University in 1983, majoring in Biochemistry and Pharmacology.  She went on to do her doctoral studies at the Department of Medicine, Austin Hospital with Professor Frederick A. O. Mendelsohn, graduating with a PhD in 1989 from the University of Melbourne.  She was then awarded the NHMRC C.J. Martin Postdoctoral Fellowship in 1991 to train with Professor Tomas Hokfelt at the Department of Histology, Karolinska Institutet.  She established her own research laboratory at the Howard Florey Institute and was appointed an NHMRC research fellow in 1999 and senior research fellow in 2004. She was recruited to the Department of Physiology, Monash University in 2011 where she holds a joint appointment as senior lecturer as well as NHMRC senior research fellow.

Dr Chai has published more than 125 research papers and book chapters and is an inventor on 6 patents.  Her research is supported by NHMRC and NHF grants.

Research Interests

Metallopeptidases cleave amino acids from either the N- and C-termini of peptide substrates to either generate or degrade biologically active peptides and the activity and their activities are dependent on the presence of zinc in the catalytic sites. These enzymes play important roles in the body and alterations in their activities can impact on a diverse range of physiological processes in both healthy and diseased states.  In recent years, our research has concentrated on 2 metallopeptidases involved in the processing of angiotensin peptides, namely angiotensin converting enzyme (ACE) and insulin-regulated aminopeptidase (IRAP). Our findings have revealed previously unsuspected and more widespread roles for these enzymes, particularly their involvement in memory processing, glucose homeostasis, cardiovascular function and water and electrolyte balance.  We have a drug development program targeting one of these enzymes (IRAP) and have identified two families of lead compounds that await development into a new class of clinically effective cognitive enhancers useful in treating dementia (patents filed).

Our current research is focussed on elucidating novel physiological and pathophysiological roles for ACE and IRAP using a whole series of research tools developed in the laboratory including IRAP antibodies, small molecule IRAP inhibitors and tissue-specific knockout mouse lines.

Research Projects

I. Development of new classes of memory enhancers 
This body of work will build on our laboratory’s successful drug discovery program to identify new classes of cognitive enhancers using state of the art techniques including in silico drug screening, docking, high throughput fluorimetric enzyme assays, site-directed mutagenesis and pharmacokinetic analysis.

                        
                                                                                                                                                                               

2. Efficacy of IRAP inhibitors in animal models of memory loss
Memory loss can result from a number of factors - normal aging process (mild cognitive impairment), disease (Alzheimer’s dementia, AD) and damage (stroke, brain trauma). The effectiveness of newly developed cognitive enhancers in attenuating memory deficits observed in these conditions will be comprehensively investigated using 2 mouse models of AD and a range of memory paradigms including the novel object recognition, swim maze, Y maze and inhibitory avoidance tasks. 
 

3. Role of IRAP in memory processing
Although it is well-established that inhibition of IRAP leads to facilitation of memory, the role of the enzyme in memory processing has not been elucidated. It has also not been clearly established which stages of memory formation process (acquisition, consolidation and/or recall) the IRAP inhibitors were most effective at. This project will investigate the mechanism of action by which IRAP inhibitors enhance memory and reverse memory loss. The techniques used range from Western blot analysis, morphological determination of spine densities, immunohistochemistry, electrophysiology (LTP) to whole animal behavioural assays.

  

4. Role of IRAP in AD
Our newly discovered IRAP inhibitors are currently being developed as potential therapeutic agents for symptomatic treatment of AD.  However, it is not known if IRAP contributes to the pathophysiology of AD by regulating the levels of A (in its role as a peptidase), altering the trafficking of APP or A in neurons (in its role as a regulator of vesicular transport) or participating in the inflammation process.  This project will investigate the role of IRAP in the processing and deposition of amyloid plaques in mouse models of AD using the techniques - immunohistochemistry, ELISA, Western blot analysis and real-time PCR.

 

 5.  Role of IRAP in ischemic damage 
Stroke is Australia’s second greatest cause of death after coronary heart disease and is a leading cause of disability. We have three independent observations that provide clear evidence for the involvement of IRAP in ischemic damage (1) markedly reduced damage in the brains of the IRAP KO mice following middle cerebral artery occlusion, (2) IRAP inhibitor treatment attenuating volume of ischemic damage and (3) the detection of IRAP immunostaining in activated astrocytes and microglia after damage.  This project will elucidate a role for IRAP in the brain following focal or global ischemia and develop the concept of IRAP inhibitors as a potential treatment.  The techniques used include primary cell culture, Western blot analysis, immunohistochemistry, real-time PCR and ELISA.

6.  Role of IRAP in cardiovascular function
We have recent preliminary data that suggest that the IRAP KO mice have enhanced vascular reactivity to vasodilators, decreased ability to retain and deposit fat and are less susceptible to the development of atherosclerosis.  We will determine the cardiovascular phenotype of the IRAP KO mice and investigate the effect of IRAP inhibitors on atherosclerosis and obesity related diseases.  The techniques used include Western blot analysis, real-time PCR, ELISA, to whole animal surgeries and in vitro/in vivo measurements of cardiovascular function.

 

Research Team

 

Group members (L-R): Broden Morgan (PhD student), Vi Pham (postdoctoral fellow), Siew Yeen Chai (NHMRC senior research fellow), Peta Burns (research assistant)
Absent: Holly Yeatman (PhD student) Michelle Chen (PhD student)

 

Key Publications

1.    Albiston, A.L., McDowall, S.G., Matsacos, D., Sim, P., Clune, E., Mustafa, T., Lee, J., Mendelsohn, F.A.O., Simpson, R.J., Connolly L.M. and Chai,  S.Y. 2001  Evidence that the angiotensin IV (AT4) receptor is the enzyme insulin regulated aminopeptidase.  Journal of Biological Chemistry 276(52):48623-48626.

2. 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.O., Parker, M.W. and Chai, S.Y.  2008  Identification and characterization of a new class of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase. FASEB Journal 22(12):4209-4217.

3. Albiston, A.L., Diwakarla, S.,  Fernando, R.N., Mountford, S.J.,  Yeatman, H.,  Morgan, B., Pham, V., Holien, J.K., Parker, M.W., Thompson, P.E. and  Chai, S.Y. 2011  Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers.  British Journal of Pharmacology, in press

Select Recent Publications

4. Albiston, A.L., Fernando, R.N., Yeatman, H.R., Burns, P., Ng, L., Daswani, D., Diwakarla, S., Pham, V., and 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 93(1):19-30.

5. Albiston, A.L., Pham, V., Ye, S., Ng, L., Lew, R.A., Thompson, P.E., Holien, J.K., Morton, C.J., Parker, M.W. and Chai, S.Y.  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 78(4):600-7.

6. de Bundel, D., Smolders, I., Yang, R., Albiston, A.L., Michotte, Y. and Chai, S.Y.  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 92(1):19-26.

7. Pham, V., Burns, P., Albiston, A.L., Yeatman, H.R., Ng, L., Diwakarla, S. and Chai, S.Y. 2009  Reproduction and Maternal Behaviour in Insulin Regulated Aminopeptidase (IRAP) Knockout Mice, Peptides 30(10):1861-1865.

8. Segura, E., Albiston, A.L., Wicks, I.P. Chai S.Y. and Villadangos J.A.  2009 Different cross-presentation pathways in steady-state and inflammatory dendritic cells.  Proceedings of the National Academy of Science USA 106(48):20377-81.

9. Fernando, R.N., Albiston, A.L. and Chai, S.Y. 2008 The insulin-regulated aminopeptidase IRAP is co-localised with GLUT4 in the mouse hippocampus - potential role in modulation of glucose uptake in neurons?  European Journal of Neuroscience 28:588–598.

10. Jenkins, T.A. and Chai, S.Y.  2007 Effect of chronic angiotensin converting enzyme inhibition on spatial memory and anxiety-like behaviours in rats.  Neurobiology of Learning and Memory, 87:218-224.

11. Fernando, R., Luff, S.E., Albiston, A.L. and Chai, S.Y.  2007   Sub-cellular localization of insulin regulated aminopeptidase, IRAP, to vesicles in neurons. Journal of Neurochemistry, 102(3):967-76.

12. Peck, G.R., Ye, S., Pham, V., Fernando, R.N., Macaulay, L.S., Chai, S.Y. and Albiston, A.L.  2006   Interaction of the Akt substrate, AS160, with the GLUT4 vesicle marker protein, IRAP.   Molecular Endocrinology, 20(10):2576-83.