Liver cirrhosis is a chronic and degenerative disease that can lead to inability of the liver to perform its biochemical function thus severely affecting the quality of patients' life. Currently, liver biopsy is the gold standard in determining the presence of liver cirrhosis. However, liver biopsy is both invasive and costly, with complications. Also, this procedure is difficult for those who have coagulation disorder. Thus, how to best evaluate and manage the increasing numbers of patients with chronic liver diseases is 1 of the major clinical problems. Clearly, there is a great need for the invention of accurate non-invasive tests that can replace liver biopsy. Interestingly, we have found that DcR3, an anti-apoptotic molecule in the TNF receptor family, was specifically expressed in regenerating modules of cirrhotic livers and that the serum level of DcR3 was elevated in patients with cirrhosis and cirrhosis associated complications. Therefore, we hypothesize that DcR3 might provide a survival advantage of liver cells during the development of cirrhosis and that the serum level of DcR3 might be useful to predict cirrhosis in patients with chronic liver diseases. To investigate this, we propose to study 2 aims in this Phase-I feasibility study. First, we propose to develop a well characterized rapid immunological assay and validate it in accordance with the regulatory guidelines so that the assay can be adapted in future clinical settings. Second, using this assay, we propose to evaluate the level of DcR3 in archived sera of hepatitis C virus infected patients with or without cirrhosis to calculate whether the assay will have any clinical value to predict cirrhosis with high sensitivity and specificity. Also, we propose to correlate the serum level of DcR3 with the severity of fibrosis in these patients. If the serum level of DcR3 is useful to predict cirrhosis in patients with chronic liver diseases, the DcR3 assay as a stand alone test or as an addition to the biochemical tests of inflammation and fibrosis, will further aid clinicians to better evaluate clinical manifestation of chronic liver diseases. Moreover, investigation of DcR3 expression during the progression of cirrhosis might further provide insight into the mechanism underlying the pathogenesis of cirrhosis and hepatocarcinogenesis as DcR3 is known for its anti-apoptotic activity. The inhibition of DcR3 during the progression of cirrhosis might represent a new therapeutic approach to slow down cirrhosis and thus prevent carcinogenesis. Undoubtedly, the successful completion of Phase-I SBIR feasibility study will lay the groundwork for our future Phase-II SBIR study and also demonstrate the potential for future commercialization of ELISA as a diagnostic tool to evaluate patients with chronic liver diseases. If the serum level of DcR3 can be effective in the assessment of patients with chronic liver disease, this will aid clinicians in deciding the proper course of therapeutic intervention thus increasing the success rate of therapy and reducing the burden of medical care costs, as well as enhancing the quality of the patient's life. Project Narrative: Liver cirrhosis is a degenerative and irreversible disease that can impair the liver function thus gravely affecting the quality of patients' life. Liver biopsy is used to determine the presence of cirrhosis in patients with chronic liver disease but this procedure is invasive and expensive with bleeding complication. Therefore, there is a great need for the invention of cost-effective non-invasive tests that can replace liver biopsy. We speculate that the serum level of soluble receptor protein called DcR3 might be useful to predict cirrhosis with high sensitivity and specificity. Therefore, we propose to develop a well validated assay to measure the level of DcR3 in chronic hepatitis patients with or without cirrhosis. If the serum level of DcR3 can be effective in the assessment of patients with cirrhosis, this will greatly aid clinicians in deciding the proper course of therapeutic intervention thus increasing the success rate of therapy and reducing the burden of medical care costs, as well as enhancing the quality of the patient's life. ? ? ?
| Kim, S; Kotoula, V; Hytiroglou, P et al. (2009) Significance of increased expression of decoy receptor 3 in chronic liver disease. Dig Liver Dis 41:591-8 |
| Macher-Goeppinger, Stephan; Aulmann, Sebastian; Wagener, Nina et al. (2008) Decoy receptor 3 is a prognostic factor in renal cell cancer. Neoplasia 10:1049-56 |
