Dr. Yu Wang

Protein biomarker discovery in obesity and its related diseases

Obesity and its associated Type 2 Diabetes and cardiovascular disorders are reaching an epidemic proportion and has caused enormous health burden to our society. However, due to the lack of a simple and reliable way to for early detection of these deadly diseases, many patients remain undiagnosed until they develop various complications, especially cardiovascular diseases, which are becoming the top killer in the aging population. During the last several years, using Proteomics- and Genomics-based approaches we have identified a panel of novel circulating biomarkers that can predict the onset of T2DM and its associated cardiovascular disorders (Eur Heart J. 2008; ATVB 2008; Mol Endocrinology 2007; Clinical Chemistry 2006 and 2007; Circulation 2007; J Clin Endocrinol Metab 2009). These biomarkers are expected to be valuable in large-scale risk assessment, early diagnosis and therapeutic guidance of T2DM and cardiovascular diseases. We are now on the way to develop antibody-based immunoassays for large-scale risk assessment, early diagnosis and therapeutic guidance of T2DM and cardiovascular diseases. Ongoing projects will utilize advanced mass spectrometry-based technology, such as iTRAQ and SILAC for high throughput protein biomarker discovery and characterization..
Structural and functional elucidation of adipokines

Adipokines are a group of molecules selectively secreted from fat cells and play a central role in the regulation of systemic energy metabolism and cardiovascular homeostasis. Dysregulated productions and actions of many adipokines have been implicated in obesity and its related metabolic and cardiovascular dysfunctions. Our group has identified a series of novel adipokines, especially those with both diagnostic and therapeutic values in clinical medical conditions associated with obesity. Our ongoing structural and functional studies are focusing on two of these adipokines, adiponectin and lipocalin-2.

Adiponectin is an important adipokine with multiple therapeutic potentials in obesity-related diseases. An important contribution from our group to adiponectin field is the discovery of the therapeutic values of adiponectin in fatty liver diseases (Journal of Hepatology 2010; Hepatology 2008; Proteomics, 2004; Journal of Clinical Investigation 2003; US Patent 20040023854). In addition, we have characterized the detailed posttranslational modifications occurred within the collagenous domain of this protein, which function in a cooperative manner to facilitate the oligomerization and intracellular assembly of adiponectin oligomers (JBC 2001, 2005 and 2006). Using affinity chromatography and MudPIT approaches, a series of novel adiponectin-binding proteins from human plasma involved in regulating the bioavailability as well as biological activities of adiponectin have been discovered (Proteomics, 2006). In collaboration with Prof Alok Mitra (University of Auckland), the 3-dimensonal structure of murine adiponectin has been determined at resolutions of ~18Å and ~40Å respectively (JMB, 2008).

Our earlier study has demonstrated that lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance and hyperglycemia in humans (Clinical Chemistry, 2006). Our recent work demonstrates that lipocalin-2 is a blood-borne adipokine critically involved in the pathogenesis of obesity-associated inflammation, insulin-resistance, and metabolic disorders (Diabetes, 2009). One of our ongoing projects is to investigate the potential causative roles of lipocalin-2 in obesity-related cardiovascular dysfunctions (Diabetes, 2010). Our results suggest that targeting this molecule may help to design effective therapeutics for combating obesity-related metabolic and cardiovascular diseases (US Patent 7645616).
Drug development and evaluation in obesity-related breast cancer diseases

Breast cancer is the most frequent cancer and represents the second leading cause of cancer death among women. Recent evidences suggest that dys-regulated adipokine production from fat cells represents an important molecular mechanism linking obesity with various associated carcinogenesis. We have investigated the role of adiponectin in the pathogenesis of breast cancer development, using both nude mice models implanted with human breast carcinoma cells and transgenic PyVT mice with spontaneous development of mammary tumors. Our studies revealed that adiponectin could potently inhibit the proliferations of both estrogen receptor-positive and estrogen receptor-negative human breast carcinoma cells. Moreover, in vivo administration of adiponectin significantly attenuated the mammary tumor growth in nude mice implanted with human breast carcinoma cells. These evidences suggest a potential therapeutic role for adiponectin in the treatment of breast cancer (Cancer Research 2006, Cell Research 2007, Carcinogenesis 2008). Using our established mammary tumor mice models, we have been screening drugs that have potentials against obesity-related carcinogenesis. A drug compound has been discovered to act as a novel histone deacetylase inhibitor, specifically targeting Wnt/beta-catenin signaling pathway, and hold a great therapeutic potential for obesity-related breast cancer disease (Cancer research, 2010).
Functional characterization of SIRT1, an anti-aging protein, in metabolic and cardiovascular diseases

SIRT1 is a class III deacetylase with anti-aging functions. This protein is involved in regulating a wide range of cellular processes, such as cell cycle progression, transcriptional silencing, redox balances and energy homeostasis. Our recent study has established a role of SIRT1 in blocking the vascular aging process by targeting LKB1, a serine/threonine kinase and tumor suppressor (Circulation Research, 2010). In particular, a series of endothelial-specific SIRT1 gain- and loss-of function mice models have been established. We plan to use these valuable research tools for drug discovery and development in aging-related vascular diseases, including atherosclerosis, myocardial infarction and stroke. In addition, we have also established a series of adipose-specific SIRT1 transgenic and knockout mice for characterizing the potentials of this protein as a drug target for aging-related metabolic diseases.

*Assistant Professor of Pharmacology & Pharmacy,* The University of Hong Kong
Assistant Professor Dr. Yu Wang MBChB, MSc, Ph.D.	Dr. Yu Wang Contact me
Memberships: American Diabetes Association Professional Section American Association for the Advancement of Science American Society for Biochemistry and Molecular Biology
Research interests :
Protein biomarker discovery in obesity and its related diseases Obesity and its associated Type 2 Diabetes and cardiovascular disorders are reaching an epidemic proportion and has caused enormous health burden to our society. However, due to the lack of a simple and reliable way to for early detection of these deadly diseases, many patients remain undiagnosed until they develop various complications, especially cardiovascular diseases, which are becoming the top killer in the aging population. During the last several years, using Proteomics- and Genomics-based approaches we have identified a panel of novel circulating biomarkers that can predict the onset of T2DM and its associated cardiovascular disorders (Eur Heart J. 2008; ATVB 2008; Mol Endocrinology 2007; Clinical Chemistry 2006 and 2007; Circulation 2007; J Clin Endocrinol Metab 2009). These biomarkers are expected to be valuable in large-scale risk assessment, early diagnosis and therapeutic guidance of T2DM and cardiovascular diseases. We are now on the way to develop antibody-based immunoassays for large-scale risk assessment, early diagnosis and therapeutic guidance of T2DM and cardiovascular diseases. Ongoing projects will utilize advanced mass spectrometry-based technology, such as iTRAQ and SILAC for high throughput protein biomarker discovery and characterization.. Structural and functional elucidation of adipokines Adipokines are a group of molecules selectively secreted from fat cells and play a central role in the regulation of systemic energy metabolism and cardiovascular homeostasis. Dysregulated productions and actions of many adipokines have been implicated in obesity and its related metabolic and cardiovascular dysfunctions. Our group has identified a series of novel adipokines, especially those with both diagnostic and therapeutic values in clinical medical conditions associated with obesity. Our ongoing structural and functional studies are focusing on two of these adipokines, adiponectin and lipocalin-2. Adiponectin is an important adipokine with multiple therapeutic potentials in obesity-related diseases. An important contribution from our group to adiponectin field is the discovery of the therapeutic values of adiponectin in fatty liver diseases (Journal of Hepatology 2010; Hepatology 2008; Proteomics, 2004; Journal of Clinical Investigation 2003; US Patent 20040023854). In addition, we have characterized the detailed posttranslational modifications occurred within the collagenous domain of this protein, which function in a cooperative manner to facilitate the oligomerization and intracellular assembly of adiponectin oligomers (JBC 2001, 2005 and 2006). Using affinity chromatography and MudPIT approaches, a series of novel adiponectin-binding proteins from human plasma involved in regulating the bioavailability as well as biological activities of adiponectin have been discovered (Proteomics, 2006). In collaboration with Prof Alok Mitra (University of Auckland), the 3-dimensonal structure of murine adiponectin has been determined at resolutions of ~18Å and ~40Å respectively (JMB, 2008). Our earlier study has demonstrated that lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance and hyperglycemia in humans (Clinical Chemistry, 2006). Our recent work demonstrates that lipocalin-2 is a blood-borne adipokine critically involved in the pathogenesis of obesity-associated inflammation, insulin-resistance, and metabolic disorders (Diabetes, 2009). One of our ongoing projects is to investigate the potential causative roles of lipocalin-2 in obesity-related cardiovascular dysfunctions (Diabetes, 2010). Our results suggest that targeting this molecule may help to design effective therapeutics for combating obesity-related metabolic and cardiovascular diseases (US Patent 7645616). Drug development and evaluation in obesity-related breast cancer diseases Breast cancer is the most frequent cancer and represents the second leading cause of cancer death among women. Recent evidences suggest that dys-regulated adipokine production from fat cells represents an important molecular mechanism linking obesity with various associated carcinogenesis. We have investigated the role of adiponectin in the pathogenesis of breast cancer development, using both nude mice models implanted with human breast carcinoma cells and transgenic PyVT mice with spontaneous development of mammary tumors. Our studies revealed that adiponectin could potently inhibit the proliferations of both estrogen receptor-positive and estrogen receptor-negative human breast carcinoma cells. Moreover, in vivo administration of adiponectin significantly attenuated the mammary tumor growth in nude mice implanted with human breast carcinoma cells. These evidences suggest a potential therapeutic role for adiponectin in the treatment of breast cancer (Cancer Research 2006, Cell Research 2007, Carcinogenesis 2008). Using our established mammary tumor mice models, we have been screening drugs that have potentials against obesity-related carcinogenesis. A drug compound has been discovered to act as a novel histone deacetylase inhibitor, specifically targeting Wnt/beta-catenin signaling pathway, and hold a great therapeutic potential for obesity-related breast cancer disease (Cancer research, 2010). Functional characterization of SIRT1, an anti-aging protein, in metabolic and cardiovascular diseases SIRT1 is a class III deacetylase with anti-aging functions. This protein is involved in regulating a wide range of cellular processes, such as cell cycle progression, transcriptional silencing, redox balances and energy homeostasis. Our recent study has established a role of SIRT1 in blocking the vascular aging process by targeting LKB1, a serine/threonine kinase and tumor suppressor (Circulation Research, 2010). In particular, a series of endothelial-specific SIRT1 gain- and loss-of function mice models have been established. We plan to use these valuable research tools for drug discovery and development in aging-related vascular diseases, including atherosclerosis, myocardial infarction and stroke. In addition, we have also established a series of adipose-specific SIRT1 transgenic and knockout mice for characterizing the potentials of this protein as a drug target for aging-related metabolic diseases.
Three dimensional structures of adiponectin (Mazdak Radjainia, Yu Wang, Alok K. Mitra. JMB, 2008)
Dr. Y. Wang and her research associates


Selected Publications :
CLICK HERE FOR MORE PAPERS Zhou M, Xu A, Lam KS, Tam PK, Che CM, Chan L, Lee IK, Wu D, Wang Y. Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin. Journal of Hepatology. available online: 4-AUG-2010 DOI information: 10.1016/j.jhep.2010.05.034 Zu Y, Liu L, Lee, MY, Xu C, Liang Y, Man RY, Vanhoutte PM, Wang Y. SIRT1 Promotes proliferation and prevents senescence through targeting lkb1 in primary porcine aortic endothelial cells. Circulation Research. 2010;106(8):1384-93. (Featured article) Law IK, Xu A, Lam KS, Berger T, Mak TW, Vanhoutte PM, Liu JT, Sweeney G, Zhou M, Yang B, Wang Y. Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity. Diabetes. 2010;59(4):872-82 Chow KH, Sun RW, Lam JB, Li CK, Xu A, Ma DL, Abagyan R, Wang Y., Che CM. A gold(III) porphyrin complex with antitumor properties targets the Wnt/beta-catenin pathway. Cancer Research. 2010, 70(1):329-37. (Co-corresponding author) Law IK, Liu L, Xu A, Lam KS, Vanhoutte PM, Che CM, Leung PT, Wang Y.* Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects of sirtuins. Proteomics. 2009, 9(9):2444-56. Lam JB, Chow KH, Xu A, Lam KS, Liu J, Wong NS, Moon RT, Shepherd PR, Cooper GJ and Wang Y. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities. PLoS ONE. 2009, 4(3):e4968. Liu J, Lam JB, Chow KH, Xu A, Lam KS, Moon RT and Wang Y. Adiponectin stimulates Wnt inhibitory factor-1 expression through epigenetic regulations involving the transcription factor specificity protein 1. Carcinogenesis, 2008, 29(11):2195-202 Zhou M, Xu A, Tam PK, Lam KS, Chan L, Hoo RL, Liu J, Chow KH and Wang Y. Mitochondria dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology, 2008, 48(4):1087-96. Wang Y., Lam KS, Kraegen EW, Sweeney G, Zhang J, Tso AW, Chow WS, Wat NM, Xu JY, Hoo RL and Xu A. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clinical Chemistry. 2007, 53: 34-41. Wang Y., Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ and Xu A. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Research. 2006, 66:11462-70. (Corresponding author) CLICK HERE FOR MORE PAPERS
Collaborations :
Dr Alok Mitra, Prof Garth JS Cooper, School of Biological Sciences, The University of Auckland, New Zealand Professor Raili Myllylä, Department of Biochemistry, University of Oulu, Finland Prof. Randall T. Moon, HHMI and Dept. of Pharmacology, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA Prof. Edward Kraegen, Garvan Institute of Medical Research, The University of New South Wales Sydney, Australia
Other Information :
Funding sources: GRF 777908 and 778007 from the Earmarked Research Grants of the Research Grants Council, Hong Kong
Useful Links :
ExPASy Proteomics Server NCI 2DWG Image Meta-Database i-mass Protocol Online

-Last update on Mar 2011-

Selected Publications :

Collaborations :

Other Information :

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