Drug Discovery and Membrane Physiology

  Research Areas


Research Interest
            Our laboratory is dedicated to the exploratory studies on membrane transport under both physiological and pathological conditions using multidisciplinary approaches. The ultimate aim of the laboratory is to provide deeper insight into regulation of membrane transport and signaling as well as identification of possible drug targets as well as candidates. Specific research areas of interest are listed below

1. Membrane Transport; Kinetics of Transport; Molecular Basis of Transporter-Substrate Interaction

            Our work is focused on understanding the molecular and cellular physiology of organic electrolyte transport in the kidney. The kidney, particularly the proximal tubule, actively secretes a wide array of organic ions, largely derived from dietary or pharmaceutical sources. Thus, it plays an important role in determining the efficacy of therapeutic drugs. Moreover,  many of these compounds are toxic and renal secretion of these xenobiotic compounds plays a critical role in protecting the body from these agents. However, this task also places the kidney in harms, and the development of nephrotoxicity is one consequence of the renal secretion of what are typically referred to as organic anions and organic cations. We are currently studying the renal transport of organic anions and cations at several different levels of biological organization.
            Cellular Level: We use cultured cells (including primary renal cells, continuous renal cell lines, and generic cells lines for the expression of cloned transport proteins) in studies of the activity and regulation of transport activity.
            Tissue Level: We use isolated, intact renal proximal tubules (single non-perfused tubules) to study the process of organic electrolyte secretion as it occurs in the native renal epithelium.
            Organ Level: We use whole animal to study and /or confirm the results obtained from both cellular and tissue levels.
Our studies employ a wide array of methodologies, including
kinetic assessment of membrane transport in cultured cells, in single tubule segments using radiometric approach and molecular biology to identify the expression of protein transporters under the desired conditions.

2. Salt and water handling associated with the development of hypertension and diabetic nephropathy

            Physiological and pharmacological functions of membrane channels and transporters with special focus on their impact on salts and water handling associated with development of diseases such as hypertension, diabetisnephropathy. In addition, the behavior of xenobiotic compounds including their uptake, tissue distribution, toxicity and elimination are also concerned.

 

 

3. G-protein coupled receptor physiology

            G-protein coupled receptors (GPCRs) are the current major drug target. The understanding of GPCRs signaling may provide a novel therapeutic approach for several diseases. The key interest of our group is the significance of cell-surface GPCR distribution pattern in both physiological and pathological conditions.  To address these issue, we employ wide range of approach including cell physiology, cellular imaging & image processing, mathematical modeling and chemical biology. We also focus on the physiological function of GPCR dimerization and oligomerization, especially Angiotensin receptor type I (AT1R), by using synthesized dimeric and oligomeric ligand.

4. Target-based drug discovery for diarrhea, polycystic kidney disease and thalassemia

            Advent in molecular biology and complete human genome sequencing  have expedited identification and validation of genes as well as their protein counterparts as specific targets for development of novel therapy. The first areas of research is cystic fibrosis transmembrane conductance regulator (CFTR) -based drug discovery. CFT is a cAMP-activated chloride channels abundantly expressed in epithelia of airways, intestine and kidneys. It has been validated as a pharmacological target for development of male contraceptives as well as treatment of diarrhea and polycystic kidney disease.  Our aims are to identify and characterize pharmacological properties of novel CFTR inhibitors out of structurally diverse compounds present in nature. With closed collaboration with chemists, we are able to develop series of natural product-based CFTR inhibitors with improved potency and favorable pharmacological characteristics. A multitude of experimental techniques and in vitro and in vivo models has been employed to investigate mechanism of actions and demonstrate potential utility of the lead compounds.
Another subject of our research is the development of  oligomer/polymers of carbohydrate for therapeutic purposes. We currently investigate the effect of different types of carbohydrate oligomer/polymer on immune and gastrointestinal systems as well as the interaction between the two systems. Data from this study could form the basis of application of these oligomer/polymer as therapeutics for immune or inflammation-related disorders or food supplement to promote the gut health in normal individuals.   
            Another research focus is placed on the drug discovery of thalassemia. Thalassemia is a genetic disease caused by the abnormality in hemoglobin synthesis. Beta-thalassemia is one form of thalassemia resulted from mutations in genes encoding b-globin chains. Mutant  b-globins unable to bind to a-globins, thereby reducing hemoglobin formation. Excess of a-globin chains could form toxic aggregate generating reactive oxygen species injurious to plasma membrane of erythrocytes. Damaged erythrocytes are shorter in their lifespan and more susceptible to hemolysis induced by oxidative stress or osmotic disturbance. This places thalassemic patients at high risk of developing iron overload, a dangerous complication commonly found in the patients. We investigate the adaptive response of glutathione metabolism in the red blood cells of thalassemic patients. The ultimate aim of this project is to be able to develop novel therapeutic interventions that could increase the longevity of red blood cells and decreased hemolysis as well as iron overload in thalassemia patients.


5. Muscle injury and regeneration

            Our research focuses on the effect of natural compounds derived from traditional plants on skeletal muscle regeneration in both muscle cell culture and exercise-induced rat muscle injury models. We also investigate the mechanism of natural compounds on improvement of muscle regeneration in functional and molecular levels. The outcome from our researches will provide the new therapeutic approach for enhancing muscle regeneration.


Locations: Room PR407 and PR415, Department of Physiology, Faculty of Science, Mahidol University

Principal Investigators :
Associate Professor Dr. Varanuj Chatsudthipong, Ph.D.
Dr. Sunhapas Soodvilai, Ph.D.
Dr. Chatchai Muanprasat, M.D., Ph.D.
Dr. Nithi Asavaparnumars, M.D.

Students :
Doctor of Philosophy in Physiology
Miss Promporn  Raksaseri
Miss Suticha Kittayaraksakul
Mr. Titiwat Sungkaworn
Mr.Mohammad Aly Othman
Mr. Chaowalit  Yuajit

Doctor of Philosophy in Exercise Science
Miss Tipwadee Bunprajun
Miss Pattarawan Pattamaprapanont

Medical Scholars Program (Ph.D.-M.D. Program)
Mr. Sutthipong  Sawasvirojwong
Mr. Nutthapoom  Pathomthongtaweechai

Master of Science in Toxicology
Miss Lalida  Sirianant
Miss Wachiraporn Luerang
Miss Jiriporn  Nantavichit

Grants :
- The Thailand research fund (TRF)
- The Royal golden jubilee PH.D. program
- National Science and Technology Development Agency
- Commission for Higher Education, Ministry of Education,

Publications (Last 5 years)
  1. Wongsamitkul N, Sirianant L, Muanprasat C, Chatsudthipong V. A plant-derived hydrolysable tannin inhibits CFTR chloride channel: a potential treatment of diarrhea. Pharm Res. 2010; 27:490-7.
  2. Rattanakul C, Chudoung M, Lenbury Y, Chatsudthipong V, Triampo W, Novaprateep B, Sungkaworn T. Modeling signal transduction involving G protein coupled receptors by genetic  algorithm and nonlinear spatiotemporal analysis. Recent Advances in Applied Mathematics and computational and Information Science. 2010; 1:39-44
  3. Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V. Role of estrogen in renal handling of organic cation, tetraethylammonium: in vivo and in vitro studies. Biol Pharm Bull. 2009; 32:1968-72.
  4. Rattanakul C, Sungkaworn T, Lenbury Y, Chudoung M, Chatsudthipong V, Triampo W, Novaprateep B. Nonlinear spatiotemporal analysis and modeling of signal transduction pathways involving G protein coupled receptors. International Journal of Mathematical Models and Methods in Applied Sciences. 2009; 3(3):219-229.
  5. Rattanakul C, Lenbury Y, Wollkind DJ, Chatsudthipong V. Weakly nonlinear analysis of a model of signal transduction pathway involving membrane based recptors. Nonlinear Analysis, Theory, Methods and Applications. 2009; 71 : e1620-5.
  6. Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V. Regulatory role of testosterone in organic cation transport: in vivo and in vitro studies. Biol Pharm Bull. 2009; 32(6):982-7.
  7. Chatsudthipong V, Muanprasat C. Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther. 2009; 121(1):41-54.
  8. Pariwat P, Homvisasevongsa S, Muanprasat C, Chatsudthipong V. A natural plant-derived dihydroisosteviol prevents cholera toxin-induced intestinal fluid secretion. J Pharmacol Exp Ther. 2008; 324(2):798-805.
  9. Yangthara B, Mills A, Chatsudthipong V, Tradtrantip L, Verkman AS. Small-molecule vasopressin-2 receptor antagonist identified by a g-protein coupled receptor "pathway" screen. Mol Pharmacol. 2007; 72(1):86-94.
  10. Srisawang P, Chatsudthipong A, Chatsudthipong V. Modulation of succinate transport in Hep G2 cell line by PKC. Biochim Biophys Acta. 2007; 1768(6):1378-88.
  11. Soodvilai S, Chatsudthipong A, Chatsudthipong V. Role of MAPK and PKA in regulation of rbOCT2-mediated renal organic cation transport. Am J Physiol Renal Physiol. 2007; 293(1):F21-7.
  12. Rattanakul C, Lenbury Y, Bell J, Chatsudthipong V, Triampo W, Crooke PS. Spatial Turing-type Pattern Formation in a Model of Signal Transduction Involving Membrane-based Receptors Coupled by G Proteins. Cancer Inform. 2007;2:329-43.
  13. Muanprasat C, Kaewmokul S, Chatsudthipong V. Identification of new small molecule inhibitors of cystic fibrosis transmembrane conductance regulator protein: in vitro and in vivo studies. Biol Pharm Bull. 2007; 30(3):502-7.
  14. Lungkaphin A, Lewchalermwongse B, Chatsudthipong V. Relative contribution of OAT1 and OAT3 transport activities in isolated perfused rabbit renal proximal tubules. Biochim Biophys Acta. 2006; 1758(6):789-95.