20112024

Research activity per year

Personal profile

Chinese Name

王凱亮

Biography

Dr. Wong holds Bachelor of Science (Bsc) from the University of Hong Kong. He pursued PhD in Biochemistry at Department of Biochemistry in the University of Hong Kong. 

Dr. Wong serves as a principal investigator at the School of Chinese Medicine in Hong Kong Baptist University, leading a team with expertise in biology, neuroscience and microbiome. In collaboration with clinicians and bioinformaticians, the pioneer work derived from his laboratory has led to multiple ground-breaking findings that have been published in top-tier journals with high impact, including six papers in Nature Communications, one paper in Cell Host & Microbe, one article from Nature Metabolism and one paper in Developmental Cell in the capacity of first/corresponding authors. In recognition of his research accomplishments, he was awarded the School Performance Award as Young Researcher in 2021, the President’s Award for Outstanding Performance in Early Career Researcher in 2022 and National Natural Science Foundation of China (NSFC) Excellent Young Scientist Fund (Hong Kong and Macau) in 2023. As the Principle Investigator, he has also secured around HK$17 million of research funding from competitive grant schemes in Hong Kong, Europe and the Mainland to support his multidisciplinary translational research.

Research Interests

My laboratory focuses on systematic characterization of proteases to understand the regulation of cell biology; metabolic biology to control cellular disease phenotypes suggested by human genetics; molecular mechanisms to determine roles of the microbiome in health and disease; and the molecular mechanisms uncovering patterns of human and microbial pathway regulation during disease and treatment. In my laboratory, we develop a unique research program studying the interactions between the mammalian host and its microbiome, and uncovering their effects on health and disease with the particular interests in metabolic disorders and related gastrointestinal diseases. We utilize a variety of methodologies, which encompass in-vitro experiments, animal models, preclinical animal testing, advanced metabolic profiling and genomic data analyses to uncover their functional crosstalk in human health and disease. Eventually, we will translate our findings from the bench to bedside, supporting translational research in drug discovery and traditional Chinese Medicine.

Recently, my research team has uncovered how a series of proteolytic events predominantly mediated by MT1-MMP, a key cell-surface metalloproteinase involved in extracellular remodeling, contribute to the pathogenesis of metabolic disorders including obesity and diabetes. Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of GDF15, an appetite-regulatory hormone, two decades ago created hopes for treatment of obesity. However, development of GDF15 resistance has been a big obstacle, mitigating a GDF15-centric treatment of obesity. My team has uncovered that the MT1-MMP-mediated cleavage of GFRAL, a key neuronal receptor of GDF15, controls the satiety center in the hindbrain, thereby regulating non-homeostatic appetite and bodyweight changes. This study for the first time reveals the molecular mechanism underlying the phenomenon of GDF15 resistance implicated in the pathogenesis of obesity (Nature Metabolism, 2022; research highlights in Nature Reviews Endocrinology, Nature Metabolism and Science Signaling). By in silico drug sceerning, my team has recently discovered that artesunate, an FDA-approved anti-malaria drug derived from the herbal medicine qinghaosu (artemisinin), is a powerful anti-obesity agent that safely and effectively promotes weight loss in obesity by increasing GDF15 production and sensitivity (Nature Communications, 2024).   Increased activation of MT1-MMP does not only lead to higher risks of obesity, but also causes age-associated insulin resistance by cleaving Insulin Receptor in major metabolic tissues (Nature Communications, 2022a)To the best of my knowledge, This study shows increased insulin receptor cleavage as a causative factor for age-related insulin resistance, and more importantly, to identify the novel mechanism underlying this physiological observation with important clinical implications. In addition, my team also found that the activation of MT1-MMP is a determining factor for the age-associated susceptibility to COVID-19 by regulating the proteolytic release of ACE2, a dominant entry receptor of SARS-CoV-2 (Nature Communications, 2022b). While evidence increasingly links the importance of soluble ACE2 with the infectivity of SARS-CoV-2, the underlying mechanism which regulates the release of ACE2 from the cell surface has remained elusive. The identification of MT1-MMP as a major sheddase of ACE2 in my study therefore provides novel mechanistic insights into SARS-CoV-2 infection. 

In addition to its pathological roles, I also demonstrated that the proteolytic events of MT1-MMP play an important role in various developmental processes through regulation of multiple signaling pathways. MT1-MMP controls calvarial bone development by regulation of FGF signaling (Developmental Cell, 2012; recommended by F1000Prime). In addition, MT1-MMP does not only function as a cell-surface protease for proteolysis, but also translocates into the nucleus where it functions as a transcriptional factor controlling the inflammatory responses of immune cells (Nature Communications, 2016). My previous studies are one of the first to point out the importance of proteolysis as a mechanism of altering extracellular signaling when most people regarded proteolysis as destructive only. These studies resulted in new concepts that challenged the conventional wisdom in various biological and pathological processes.

Another of my research interests focuses on the functional genomics of gastrointestinal bacteria in humans with emphasis on gut microbiota in gastrointestinal diseases and age-associated disorders. Recently, I identified gut dysbiosis as a leading cause of irritable bowel syndrome (IBS) and delineated a process through which bioactive metabolites derived from microbial catabolism of dietary amino acid triggers the development of diarrhoea-predominant IBS (Cell Host & Microbe, 2022). Although the contribution of gut dysbiosis to IBS-D has been documented, this study is the first to identify a single bacterial species and its produced metabolites that directly trigger the development of IBS-D. I further demonstrated that the interplay between gut microbiota and host factors including Nerve Growth Factor (NGF) regulates the transfer of intestinal stem cells from the quiescent niche to the proliferative niche in response to the psychological stress, contributing to the development of IBS (Nature Communications, 2019). The concept of microbe-induced IBS-D proposed herein has important implications with respect to the development of treatments for IBS and related disorders. In addition to gastrointestinal diseases, I also demonstrated that microbial shunting of amino acids into amines contributes to glucose intolerance and insulin resistance in both primates and non-primates (Nature Communications, 2023), which may pave the way for identification of innovative microbiota-based diagnostics and/or therapeutics for the management of metabolic diseases. 

Selected publications (# correspondence)

1. Guo X, Asthana P , Zhai L, Cheng KW, Gurung S, Huang J, Wu J, Zhang Y, Maharo AK, Saarma M, Ustav,M, Kwan HY, Lyu A, Chan KM, Xu P, Bian ZX, Wong HLX#. (2024) Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signaling axis, Nature Communications  [Impact factor: 16.6]

2. Zhai L*, Xiao H*, Lin CY*, Wong HLX* (*co-first), Lam YY, Gong M, Wu G, Deng Y, Ning Z, Huang C, Zhang Y, Zhuang M, Yang C, Luo J, Zhang EL, Zhao L, Zhang C, Fang Z, Lau JYN, Jia W, Zhao L, Bian Z. (2023) Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nature Communications [Impact factor: 16.6]

3. Guo X, Cao J, Wu J, Huang J, Asthana P, Wong SKK, Gurung S, Zhang Y, Wang S, Kwan HY, Lyu A, Chan KM, Huang JD, Zhou Z, Bian ZX, Yuan S, Wong HLX# (2022) Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.  Nature Communications [Impact factor: 16.6]

4. Zhai L, Huang C, Ning Z, Zhang Y, Zhuang M, Yang W, Wang X, Zhang EL, Xiao H, Zhao L, Lam YY, Chow CFW, Huang J, Yuan S, Chan KM, Yuan CS, Lau JYN, Wong HLX# (co-correspondence), Bian Z# (2022) Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis. Cell Host & Microbe [Impact factor: 30.1]

5. Guo X, Asthana P, Zhang S, Gurung S, Wong SKK, Fallah S, Chow CFW, Che S, Zhai L, Wang Z, Xin G, Jiang Z, Wu J, Zhang Y, Wu X, Xu K, Lin CY, Kwan HY, Lyu A, Zhou Z, Bian Z, Wong HLX# (2022) Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of Insulin Receptor. Nature Communications 13, 3749 [Impact factor: 16.6]

6. Chow CFW*, Guo X*, Asthana P*, Zhang S, Fallah S, Che S, Wang Z, Ge X, Jiang Z, Zhai L, Lin CY, Kwan HY, Huang T, Lyu A, Zhou Z, Bian Z, Wong HLX# (2022) Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nature Metabolism 4, 203-212 [Impact factor: 20.8]

  • Highlights of the Issue in Nature Metabolism - [Central regulation of the anorexigenic receptor GFRAL]
  • Research Highlights of Nature Reviews Endocrinology- [Negative regulator of GDF15 signaling identified]
  • Editor’s choice of Science Signaling - [Cutting down in size by not making a cut]

7. Wong HLX, Qin H, Tsang SW, Zuo X, Che S, Chow CFW, Li X. Xiao HT, Zhao L, Huang T, Lin CY, Kwan HY, Yang T, Longo FM, Lyu A, Bian Z (2019) Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling. Nature Communications 10(1):1745 [Impact factor: 16.6]

8. Wong HLX, Jin G, Zhang S, Cao R, Cao Y, Zhou Z (2016) MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Nature Communications 7:10824 [Impact factor: 16.6]

9. Chan KM*, Wong HLX* (*co-first), Jin G, Liu B, Cao R, Cao Y, Lehtl K, Tryggvason K and Zhou Z (2012). MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling in calvarial osteogenesis. Developmental Cell, 22(6); 1176-1190 [Impact factor: 13.417]

  • [recommended in F1000 Prime, F1000 factor 8.0]

 

 

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

PhD, Department of Biochemistry, The University of Hong Kong

Award Date: 1 Oct 2013

Bachelor, Biochemistry & Biotechnology, School of Biological Sciences, Faculty of Science, The University of Hong Kong

Award Date: 1 Oct 2009

Keywords

  • QP Physiology
  • Cell Metabolism
  • Cell signaling
  • RB Pathology
  • diabetes
  • obesity
  • QR180 Immunology
  • Microbiome

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