Project title
Cortisone Receptor Polymorpfisms and Gut Inflammation Modulate the Response to Therapy in Severe Alcoholic Hepatitis
Acronym & code
CRASHING (PN-III-P1-1.1-TE-2016-1196)
Funding
UEFISCDI - contract nr 107/2018
Value
450.000 lei
Duration
24 months (01/05/2018 - 30/04/2020)
Team members
Horia Stefanescu, MD, PhD - principal investigator
Adelina Horhat, MD
Petra Fischer, MD, PhD student
Andreea Bumbu, MD
Ioana Rusu, MD, PhD student
Andreea Benea, MD
Patriciu Protopopu, medical student
Sergiu Pasca, medical student
Objectives
Severe AH remains a condition with very high mortality. The only effective therapy (Prednisone) is not efficient enough as the high rate of non-responders demonstrates. Therefore, the research hypothesis behind this project is that the response to GC therapy and the prognosis in severe AH is influenced by changes of the specific GC pathway and/or by an excessive gut inflammation and bacterial translocation. Under these circumstances, our aim is to identify a personalized noninvasive profile of patients with severe AH which would allow the early prediction of the response to GC therapy.
Therefore, our main objectives are:
1. To identify a genetic SNPs profile of the GC axis associated with the response to therapy and short-term mortality in patients with severe AH.
2. To test orphan biomarkers of gut inflammation as novel noninvasive predictors of gut-blood barrier damage that will favour bacterial translocation and will influence the response to therapy and short-term mortality in patients with severe AH.
In close relationship, the secondary objectives of the study are:
1. To study the BclI, N363S, ER22/23EK, GR 9beta polymorphisms of the GR gene in relationship with the severity of AH, response to GC therapy and short term mortality;
2. To correlate the GR polymorphisms with their morphologic expression on liver tissue (assessed by IHC) in AH;
3. To correlate the IHC liver expression of GR with the severity of AH, response to GC therapy and short term mortality;
4. To study the relationship between the CBG and MDR1 polymorphisms and the resistance to GC treatment.
5. To validate gut inflammation biomarkers (especially serum and fecal calprotectin, but also lactoferrin) as predictors of response to GC therapy and short term mortality.
Activities & Milestones
A1 - Patient's evaluation and enrolment
A2 - Assessment of cortisone axis
A3 - Assessment of intestinal translocation and inflammation
A4 - Data integration and interpretation. Dissemination of results
A5 - Project management
M1 - inclusion of at least half of the patients by the mid-term of the project (12 months);
M2 - acquisition of all the laboratory reagents by the 3⁄4 of the project (18 months);
M3 - submission of manuscripts revealing results of the research after 12 and, respectively 21 months;
M4 - acceptance of intermediate and final reports by the Authority at the end of each year and at the end of the project.
