Categories:
  • Post Doctoral Position - Academic
Job Type/Arrangement:
  • Full Time
Description:

Within the Department of Immunology & Microbiology at The Scripps Research Institute in La Jolla, California, United States, the following postdoctoral position is available:


Principal Investigator: Professor Philippe Gallay, Ph.D.

E-Mail: gallay@scripps.edu

Website: http://www.scripps.edu/gallay


Background: Approximately 240 and 71 million people suffer from chronic HBV and chronic HCV infection, respectively. Chronic HBV and HCV infections represent the leading cause for hepatocellular carcinoma. Hepatocellular carcinoma carries high economic burden on society. Owing to the high risk of developing end-stage liver disease or hepatocellular carcinoma, CHB is associated with high mortality, with 880,000 deaths per year. Similarly, 500,000 people die each year from chronic HCV-related liver diseases such as liver cirrhosis or hepatocellular carcinoma. HBV initiates the neoplastic process while HCV acts as a promoter having a synergistic effect in causing hepatocellular carcinoma. The risk for hepatocellular carcinoma in chronic HBV and HCV infection is linked to liver inflammation that drives fibrosis, cirrhosis and hepatocellular carcinoma. It is the persistent inflammation and destruction of hepatocytes that leads to carcinogenesis. The risk of hepatocellular carcinoma development remains after virus elimination, especially for patients who had advanced liver cirrhosis at the time of treatment. More than 100 trials evaluating chemotherapy or targeted therapies in hepatocellular carcinoma failed to show survival advantage. Thus, it is of the utmost importance to identify novel therapeutic approaches to treat viral hepatitis-induced hepatocellular carcinoma.


Recent results from the lab: Recently our lab identified a novel class of compounds called cyclophilin inhibitors including CRV431, NV556 and Alisporivir, which possess dual therapeutic activities critical for preventing the development of viral hepatitis-induced hepatocellular carcinoma. We very recently published that cyclophilin inhibitors not only inhibit HCV and HBV replication in vitro and in vivo, but also discovered that they inhibit the development of hepatocellular carcinoma by inhibiting the development of the early steps of hepatocellular carcinoma – non-alcoholic steatohepatitis and liver fibrosis – in several mouse models that we developed in the lab.


Position: Cyclophilin inhibitors neutralize the enzymatic activity of cyclophilins, which regulate multiple cellular functions. An excellent review from Ure et al. describes in detail the plausible cellular functions of cyclophilin members that may lead to the development of non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma (Ure et al. Expert Opinion on Investigational Drugs, 29:2, 163-178, DOI: 10.1080/13543784.2020.1703948).

 

A postdoctoral position is immediately available i) to investigate the mechanisms of anti-viral hepatitis action as well as anti-liver damage action of cyclophilin inhibitors; ii) to identify which cyclophilin member (cyclophilin A, B or D) controls the development of non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma using cyclophilin knockout mice that we recently generated in the lab; and iii) to test the therapeutic safety and efficacy of cyclophilin inhibitors in various liver damage mouse models routinely used in the lab. These studies should lead to new findings that will be translated into publications, national and international presentations, and most importantly open new avenues of attractive research.


Our lab website provides additional information about the ongoing projects of our lab: http://www.scripps.edu/gallay.


Requirements: Candidates should have a Ph.D. (recent Ph.D. obtention is preferred). Please send CV to gallay@scripps.edu.


Location: La Jolla, California, USA

Within the Department of Immunology & Microbiology at The Scripps Research Institute in La Jolla, California, United States, the following postdoctoral position is available:


Principal Investigator: Professor Philippe Gallay, Ph.D.

E-Mail: gallay@scripps.edu

Website: http://www.scripps.edu/gallay


Background: Hepatitis B virus (HBV) is a major worldwide threat with over 257 million people chronically infected, and with over 887,000 deaths per year. Chronic hepatitis B causes 40% of cases of hepatocellular carcinoma, which is the second leading cause of cancer-related mortality worldwide. The current vaccine has no beneficial effect on established chronic infection. Current therapeutic treatments suppress HBV replication, but are not curative, due to the persistence of the viral covalently closed circular DNA (cccDNA) transcriptional template in infected hepatocytes in addition to the failure of chronically infected patients to develop an immune response robust and sustained enough to totally clear the infection. Therefore, most of the patients cannot interrupt their drug treatments for their entire lives.


One strategy to cure HBV consists in the elimination of HBV by killing infected cells but keeping intact non-infected cells. We developed a new strategy to hijack the viral replication machinery to kill HBV-infected hepatocytes while preserving uninfected hepatocytes. This strategy consists in infecting HBV-infected hepatocytes with adeno-associated virus vectors encoding the reverse complement open reading frame of genes of interest that will only be recognized and reverse transcribed by the HBV polymerase/reverse transcriptase present in infected cells, triggering the protein expression of the genes of interest. We developed adeno-associated virus vectors, which deliver the reverse complement open reading frame of human caspase-9 – an initiator of the apoptosis caspase pathway – into infected livers that induces the killing of HBV-infected but not uninfected hepatocytes, leading to the elimination of HBV reservoirs without damaging liver functions.


Position: We obtained solid in vitro data that demonstrates that our new approach, which consists of hijacking viral machinery strategy, kills HBV-infected cells while preserving uninfected cells. Our next step is to duplicate these attractive findings in vivo.


A postdoctoral position is immediately available to test our approach, in four distinct mouse models developed in our lab. Among them, we have i) an HBV transgenic mouse model; ii) an HBV humanized liver mouse model; iii) an adeno-associated vector-HBV transduction mouse model; and iv) a new in vivo imaging mouse model allowing in live detection of implanted bioluminescent human hepatocytes expressing HBV. The ultimate goal of these in vitro and in vivo studies is to demonstrate that this novel therapeutic strategy, which exploits the viral replication machinery to induce apoptosis and cell death, lead to the elimination of normally resilient HBV reservoirs, and eventually to a cure. These studies should also lead to numerous publications, national and international presentations, and new avenues of attractive research.


Our lab website provides additional information about the ongoing projects of our lab: http://www.scripps.edu/gallay.


Requirements: Candidates should have a Ph.D. (recent Ph.D. obtention is preferred). Please send CV to gallay@scripps.edu.


Location: La Jolla, California, USA



Education Requirement:
Ph. D.
Location:
Main Campus
Immunology and Microbiology
10550 North Torrey Pines Road
La Jolla , California 92037
US
Contact:
Philippe Gallay, Ph.D.