Professor George Chandy

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George Chandy.JPG

 

 

George Kanianthara Chandy
MBBS, PhD
Professor of  Molecular Physiology
Email: gchandy@ntu.edu.sg
Principal Investigator, Molecular Physiology Laboratory

 
 
 
 
Laboratory Staff
  • Dr Tang Yanxia, Senior Research Fellow
  • Dr Tanima Bose, Research Fellow
  • Dr Jeff Chang Shih Chieh, Research Fellow
  • Dr Bajaj Saumya, Research Fellow
  • Nandini Nallappan, Research Assistant
  • Han Jingyao, Research Assistant

 
Introduction
Professor George Chandy graduated from Christian Medical College (CMC) Vellore, one of the premier medical schools in India. After graduation, he joined a Virology laboratory at CMC which piqued his interest in research. He then pursed his PhD at the University of Birmingham, Department of Immunology. In 1983, he moved to the University of California Irvine ( UC Irvine) as a postdoctoral clinician-scientist researcher in the Division of Basic and Clinical Immunology, Department of Medicine, where he did clinical work in the Division’s Clinic while pursuing research under the laboratory of the Division Chief, Professor Sudhir Gupta. He moved to the Department of Physiology and Biophysics at UC Irvine in 1990 and was eventually promoted to Professor.
Prof Chandy is an elected member in the Henry Kunkei Society and has been awarded the Athalie Clarke Award: Excellence in Research. His paper has been published on various highly distinguished publications such as Nature, Science and Journal of Clinical Investigation. He has also been listed in Thomson Reuters’s report on World Most Influential Scientific Minds 2014 as one of the Highly Cited Researchers.
Prof Chandy is currently a Professor of Molecular Physiology at Lee Kong Chian School of Medicine, NTU.
 
Research Focus

Between academic research and the completion of human phase-1 safety trials (when drugs are often licensed by biopharmaceutical companies) lies a “valley of death”, where promising discoveries frequently stall. Prof Chandy and his team aim is to bridge this valley of death. To achieve this goal,  they are building a Translational Research Program focused on potassium channel-targeted therapeutics for autoimmune, fibrovascular and metabolic diseases.

Potassium Channels

Potassium channels are the largest family of ion channels, with 76 genes in humans. The diversity of potassium channels in different physiological systems, coupled with their important functional roles, makes them excellent targets for selective modulation of specific tissues and functions. Their work on potassium channels employs functional assays of cell and molecular function, molecular and structural biology approaches, and pharmacology with in vivo assessment of efficacy in animal studies. They are currently focused on developing therapeutics that act on two potassium channels, Kv1.3 and KCa3.1.
Kv1.3 Channel and Autoimmune Diseases
Commonly used immunosuppressant drugs cause serious side effects because they broadly suppress the immune system. A subset of T lymphocytes called effector memory T cells (TEM cells) play a critical role in the development of these diseases. Therapeutics that selectively silence TEM cells without compromising protective immune responses against infections mediated by other T lymphocytes would have significant advantages over existing drugs. The Kv1.3 channel plays a critical role in TEM cells. They have developed specific Kv1.3 inhibitors that selectively silence TEM cells without compromising the protective immune response. They have shown the effectiveness of these drugs in treating autoimmune diseases in rodent models, and one of their drugs, ShK-186, is in human trials for autoimmune diseases (Figure 1).
Kv1.3 and Metabolic Diseases
Obesity is a global epidemic, calling for innovative and reliable pharmacological strategies. Genetic and pharmacological studies suggest that the Kv1.3 is a therapeutic target for obesity and diabetes. A genetic variation in the Kv1.3 gene is associated with elevated blood sugar, reduced insulin sensitivity and impaired smell in Caucasians. Studies in animal models support the potential role for Kv1.3 in diabetes and obesity. ShK-186, the selective and potent blocker of the Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed with a diet rich in fat and fructose. ShK-186 reduces weight gain, adiposity and fatty liver, it decreases blood levels of cholesterol, sugar, HbA1c, insulin and leptin, and it enhances peripheral insulin sensitivity. At least three mechanisms contribute to ShK-186’s therapeutic activity: increased energy expenditure by activation of brown fat; reduced inflammation of white fat, and profound changes in central energy and lipid metabolism in the liver. Their studies highlight the potential use of selective Kv1.3 blockers in the treatment of obesity. They are also developing Kv1.3 inhibitors as therapeutics to prevent and treat fatty liver disease and steatohepatitis, two common sequelae of obesity and a major reason for liver transplant.
KCa3.1 Channel and Fibrosis
The KCa3.1 potassium channel plays an important biological role in T cells, macrophages, proliferating myofibroblasts and hepatic stellate cells. They developed TRAM-34, a selective and potent inhibitor of KCa3.1. In rodent models, TRAM-34 effectively suppresses atherosclerosis, fibrosis of the liver, kidney and lung, and it reduces neuronal damage after stroke. TRAM-34 is well tolerated by rodents and also non-human primates. Further, the TRAM-34 analog Senicapoc has been shown to be safe in phase II human trials, suggesting that this class of KCa3.1 channel blockers are safe and have significant therapeutic potential. They are developing therapeutic approaches based on the KCa3.1 channel to prevent and treat liver fibrosis caused by hepatitis C viral infection, reduce fibrosis around implants and internal organs following surgery, and reduce occlusion of vascular access for patients undergoing hemodialysis. They are also determining the atomic structure of the KCa3.1 channel, which would facilitate the development of more specific and potent KCa3.1-modulating drugs.

 

 
fig1-01.jpg 
Figure 1: Left: Atomic structure of a Kv channel. Middle: Image of the sea anemone, Stichodactyla helianthus . Right: ShK-186, a peptide isolated and modified from the sea anemone, blocks Kv1.3 channels at low picomolar concentrations. It uses lysine-22 (shown in red) to occlude the channel like a cork in a bottle, and the AEEA-linker-pTyrosine (blue) provides Kv1.3 channel-specificity.
fig2-01.jpg 
 Figure 2: Left: A 6-transmembrane KCa3.1 channel subunit complexed at its C-terminus to calmodulin. The functional channel is formed of 4 KCa3.1 subunits and 4 calmodulins. Right: Triarylmethane-34 selectively blocks KCa3.1 channels at low nanomolar concentrations.
 
 

 LKCMedicine Research Spotlight

 
 
 

 
 
Key Publications
 
  1. DeCoursey TE, Chandy KG, Gupta S, Cahalan M. 1984. Voltage gated potassium channels in human T lymphocytes: A role in mitogenesis? Nature. 307:465
  2. Chandy KG, DeCoursey TE, Cahalan MD, McLaughlin C, Gupta S. 1984. Voltage-gated potassium channels are required for human T cell activation. J Exp Med. 160:369.
  3. Grissmer S, Dethlefs B, Wasmuth J, Gutman G, Goldin AL, Cahalan MD, Chandy KG.  1990. Expression and chromosomal localization of a lymphocyte K+ channel.  Proc Natl Acad Sci USA. 87:9411.
  4. Aiyar J, Withka J, Rizzi J, Singleton DH, Andrews GC, Lin W, Boyd J, Hanson DC, Simon M, Dethlefs B, Chao-lin Lee, Hall J, Hanson DA, Gutman GA, Chandy KG.  1995. Topology of the pore pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins.  Neuron 15:1169. 
  5. Wulff H, Miller M, Grissmer S, Hansel W, Cahalan MD, Chandy KG.  2000. Design of a selective inhibitor of the intermediate-conductance calcium-activated K+ channel, IKCa1: A potential immunosuppressant.  Proc Natl Acad Sci USA. 97:8151.
  6. Wulff H, Calabresi P, Beeton C, Yun S, Allie R, Pennington M, Chandy KG. 2003. The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J Clin Invest. 111:1703.
  7. Beeton C, Wulff H, Standifer NE, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus H-G, Nepom, GT, Gutman GA, Calabresi PA, Chandy KG. 2006. Kv1.3 channels: Therapeutic target for T cell-mediated autoimmune diseases Proc Natl Acad Sci USA. 103:17414.
  8. Toyoma K, Wulff H, Chandy KG, Azam P, Raman G, Saito T, Fujiwara Y, Mattson DL, Das S, Melvin JE, Pratt PF, Hatoum OA, Gutterman DD, Harder DR, Miura H. 2008. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J Clin Invest. 118:3025-3037.
  9. Upadhyay SK, Eckel-Mahan K, Mirbolooki MR, Tjong I, Griffey SM, Schmunk G, Koehne A, Halbout B, Iadonato S, Pedersen B, Borrelli E, Wang PH, Mukherjee J, Sassone-Corsi P, Chandy KG. 2013. Selective Kv1.3 blocker as therapeutic for obesity and insulin resistance. Proc Natl Acad Sci USA. 110:E2239-48.
  10. Chhabra S, Chang J, Nguyen HM, Redwan H, Tanner MR, Londono LM, Estrada R, Dhawan V, Chauhan S, Upa​dhyay SK, Wulff H, Iadonato SP, Gutman GA, Beeton V, Pennington MW, Norton RS, Chandy KG. 2014. Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases. FASEB J. 28:3952-3964.