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Research Findings

 

 

Intestinal Disease:

Much attention is being focused on inflammatory bowel diseases in view of their increasing prevalence in our country. In view of the controversial relevance of Mycobacterium avium ss paratuberculosis (MAP) in the etiology of Crohn’s disease (CD), we examined intestinal biopsy tissue for MAP-specific IS 900 sequence and obtained results that do not support the etiological role of MAP in the pathogenesis of CD in Indian patients (Ind. J. Gastroenterol 2009; 28: 169-174). Even though IL23 R polymorphisms are reported to enhance patient susceptibility to CD, we did not find any correlations between them (Journal of Gastroenterology and Hepatology, 2010; 26:694-699). We have thus embarked on obtaining detailed data on intestinal microflora in patients diagnosed for inflammatory bowel disease employing next generation sequencing.

 

Gastrointestinal Cancer:

Mutations in K-RAS gene are implicated in carcinogenesis and patients with such mutations do not show response to antibody treatment. Hence we have initiated studied to analyze K-RAS gene mutations in colorectal cancer patients. In our preliminary studies significant association could be noted between K-RAS gene mutations and colorectal tumerigenesis in 21% of patients. We have also initiated studies to obtain miRNA profiles in GI malignancies as well as obtain comparative miRNA profiles in pancreatic cancer and chronic pancreatitis. Towards evolving personalized therapy, we have screened general populations for CYP2C19 polymorphism in South Indian population and noted that 15% of them have mutations in the gene (J Assoc Physicians of India 2011; 59). In continuation of this observation we have initiated studies to evaluate CYP2C19 polymorphism in relation to proton pump inhibitors (Project funded by Indian Council of Medical Research).

 

Pancreatic Disease:

One of the primary intents of the Institute is to develop technological resources and applications of biotechnology that may be used in clinical trials to improve survival rates of patients with pancreatic disease.

 

Chronic pancreatitis:

Chronic pancreatitis (CP) is a progressive inflammatory disease of multifactorial etiology, involving irreversible destruction of exocrine tissue and its replacement by fibrous tissue, leading to endocrine dysfunction. Total/partial pancreatectomy to alleviate pain can cause surgically induced type 3c diabetes in these patients prompting autologous islet cell transplantation to preserve endocrine functions. However, the limited functional viability of transplanted islets necessitates further insights into molecular events related to beta-cell dysfunction in CP. We are thus conducting studies to monitor changes in islet characters, endocrine functions and gene expression as also to unravel cytokine-mediated events during progression of CP. Results obtained in this regard would be useful in prolonging survival of transplanted islets, considering the increased prevalence of tropical calcific pancreatitis and surgical removal of pancreas in such patients in our country. This study is sponsored by Indian Council of Medical Research through a research grant.

 

Cell replacement therapy and Islet cell transplantation studies:

Considering the relevance of islet cell transplantation for treatment of diabetes associated with CP, we are conducting studies to isolate, culture and transplant islet cells. Further, the efficacy of immuno-isolatory devices as vehicles of beta cells to prevent immune rejection of transplanted islets is being evaluated in non- human primates (DBT Project# BT/PR10536/MED/ 31/26/2008). In continuation of our observation that the miR-30 family microRNAs confer epithelial phenotype to human pancreatic cells (Islets 2009; 1: 1-11), we are comparing the micro RNA profiles in islets isolated from patients diagnosed for CP and pancreatic cancer.

 

 

 

Diseases of Liver & Gall Bladder:

Viral hepatitis:

Hepatitis of viral origin is rampant in our country and has necessitated development of various vaccines towards its prevention. It is estimated that 4% of our population is infected with hepatitis B virus and nearly 2% of the population is infected with hepatitis C virus. However, adequate data is not available to relate viral loads either with the altered immune functions or the incidence of hepatocellular carcinoma associated with viral hepatitis. Thus, our research focused on (i) identification of Hepatitis virus genotype/variants in Indian populations and (ii) determination of endogenous interferon-mediated basal antiviral state in hepatitis C virus infection. These studies resulted in:

 

  • First time identification of genotype B among Hepatitis patients in local populations (Ann.Hepatol 2009; 8:269-270);
  • Development of a kit towards detection of diagnosis-escape variants of hepatitis B virus (Indian Patent # 3385/CHE/2010). Detection of occult HBV infection in false negative patients for HBV is now possible using this indigenous method.
  • A spectrum of incidentally detected hepatitis C virus infection has been identified in south Indian population (communicated to Indian Journal of Gastroenterology)
  • Establishing interrelationships between serum HBs AG level, HBV DNA level and peripheral immune cells in patients with chronic hepatitis B infection (Hepatic Medicine: Evidence and Research 2010; 2: 157-162).
  • Elucidating the mechanism involved in viral persistence of hepatitis C virus (Communicated to Intervirology). This study points to a possible link of hepatitis C infection triggering hepatocellular carcinoma
  • Genotyping of IL28β in HCV infected patients has revealed that clearance of HCV does not occur when a polymorphism is found in this gene We are also extending our research interests to understand genetic predisposition to Gilbert’s syndrome and obtain implications of host genotype in the clearance of HCV by traditional therapy. Non-alcoholic fatty liver disease (NAFLD)

 

NAFLD, a global epidemic, is highly prevalent in India with about 24% of our population affected by this disease. Since adipokines are now implicated in NAFLD,, we have determined visceral adipose tissue visfatin (Ann. Hepatol 2010; 9: 266-70).Considering that dietary vitamin B12 deficiency is a serious problem in our country, we are conducting in-depth studies to relate this deficiency to hyperhomocysteinemia-induced endoplasmic (ER) stress in NAFLD towards evolving better strategies for the prevention and management of the disease. Preliminary studies have revealed enhanced expression of ER stress markers (GRP78 and HERP) in patients diagnosed for NAFLD. Based on these observations we proposed to determine the extent of vitamin B12 deficiency and hyperhomocysteinemia in Indian patients and to relate hyperhomocysteinemia-induced ER stress to fatty infiltration of liver in NAFLD. This research is awaiting financial sanction from ICMR.

 

Cell based Therapy for Liver Cirrhosis:

Cirrhosis of the liver is a common condition in view of wide prevalence of Hepatitis B, Hepatitis C, alcohol and non alcoholic fatty liver disease. Currently only symptomatic and supportive therapy is being offered to these patients and organ transplantation of liver is the ideal treatment for end-stage liver disease. Alternatively, adult stem cell therapy experiments in animal models and patients have shown that bone marrow stem cells could solve the problem of degenerative disorders, including liver disease. Preliminary studies have shown that autologous infusion of bone marrow CD34 cells have demonstrated improvement liver functions in patients with liver failure. However further case /control studies are needed to prove effectiveness of CD34 cells in the clinical course of liver cirrhosis. With the evidence that autologus CD 34 +ve cells are beneficial, we are now exploring the better method of facilitating enriched CD 34+ve cells to the patient through mobilization from his/her own bone marrow cells or by harvesting and local diversity through infusions. A comparison is being made to study the effectiveness of mobilized peripheral blood CD34 cells by administering GCSF alone and GCSF mobilized isolated bone marrow stem cell infusion in patients with liver cirrhosis and compare with the clinical outcome of patients with cirrhosis under standard care of therapy. Results obtained in such a study may be useful in evaluating the effectiveness of stem cell therapy in patients with cirrhosis.

 

 

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