Dr G R Chandak
Profile : Dr G R Chandak is a Medical Geneticist and Group Leader at the Centre for Cellular and Molecular Biology (CSIR), Hyderabad. He received his MD in Biochemistry from Institute of Medical Sciences at Banaras Hindu University and PhD in Biochemistry from Osmania University.
His research interests include understanding the genetic and epigenetic basis of complex disorders of pancreas including chronic pancreatitis, type 2 diabetes and intermediate traits associated with them with a focus on fetal origins of adult common diseases. His group has identified novel genes associated with Tropical Calcific Pancreatitis and showed its genetic basis to be different from that in the Europeans. His research suggests that genetic basis of type 2 diabetes and intermediate traits such as obesity and insulin resistance may be differently regulated in Indians.
He has published close to 70 articles in peer-reviewed journals (including Nature, Lancet, Gut, Diabetes, Diabetologia, J Medical Genetics) and authored a number of book chapters. He is also the recipient of Andhra Pradesh Scientist Award, 2007 from AP Council for Science and Technology and is a Fellow of Andhra Pradesh Akademi of Sciences.
Abstract (Unraveling Genetic Basis Of Chronic Pancreatitis In India: A Comprehensive Approach )
Chronic pancreatitis is a heterogeneous disease with numerous etiologies. Despite variable etiologies, pancreatitis has been assumed to be an autodigestive disease secondary to premature activation of trypsinogen within the pancreas. Although, the first information about familial clustering of chronic pancreatitis was recognized in 1952, establishing its genetic basis took more than four decades when in 1996, gain of function mutations were identified in cationic trypsinogen gene (PRSS1). This also substantiated the age-old belief of pancreatitis being an autodigestive disease secondary to premature activation of trypsinogen within the pancreas. Tropical calcific pancreatitis is a type of chronic pancreatitis unique to tropical countries with a variable clinical picture compared to the commonly occurring pancreatitis due to alcohol consumption. The disease classically presents as recurrent abdominal pain in the childhood, exocrine pancreatic insufficiency, large pancreatic calculi and invariable occurrence of diabetes mellitus in the late stage. Many patients present with diabetes as the presenting symptom, an entity known as Fibrocalculous Pancreatic Diabetes (FCPD). A number of factors including malnutrition, cassava ingestion and other dietary factors have been blamed in the etiopathogenesis of this enigmatic disease. established. However, a genetic basis for TCP was ruled out initially due to absence of common mutations in PRSSI gene in these patients. We have established the genetic basis of this disease and also shown a different genotype-phenotype correlation in these patients. Close to half the patients had mutations in another gene, SPINKI coding for Pancreatic Secretory trypsin Inhibitor protein (PSTI). This suggests that cationic trypsinogen gene mutations may not have a role in TCP and on the contrary, PSTI may play a more important role in its etiopathogenesis. Similar results have subsequently been reported from other parts of the country as well as the subcontinent. The results also suggested a similar genetic basis for TCP and FCPD as well as the existence of other genetic or non-genetic factors. However, the role of mutated inhibitor in the absence of cationic trypsinogen gene mutations is the major dilemma in the field of pancreatic research.
Since, the autolysis site of trypsin still remains intact, independent role of mutated SPINKI in disease causation is not clear. We have identified mutations in the signal peptide region of CTSB in TCP patients and thus propose that mutated CTSB may affect vacuolar transport leading to mis-localization of cathepsin B to the zymogen granule compartment and consequent premature intra-pancreatic activation of trypsinogen. In addition to studying genes in isolation, we have identified several differentially regulated genes using microarray analysis and their expression at mRNA level and using a systems- biology approach identified several pathways likely to be involved in TCP.