245795S
IN THIS COLLABORATIVE CONSORTIUM, THE LAW LABORATORY WILL STUDY THE IMMUNE RESPONSES OF HEPATITIS B PATIENTS AT DIFFERENT DISEASE STAGES. CURRENTLY THERE IS LITTLE UNDERSTANDING OF HOW THE TWO MAJOR ARMS OF ADAPTIVE IMMUNE RESPONSES, CD4 T CELLS AND B CELLS, INTERACT AND ARE NEGATIVELY IMPACTED BY CHRONIC HBV INFECTION. THE LAW LAB WILL BE RESPONSIBLE FOR ASSAY DEVELOPMENT AND EXECUTION OF EXPERIMENTS ON THE B CELL RESPONSES. THE SCOPE OF WORK INCLUDES DEVELOPMENT AND PRODUCTION OF HBV SURFACE ANTIGENS (HBSAG) USEFUL FOR VARIOUS IMMUNOLOGICAL ASSAYS (ANTIBODY MEASUREMENT, CELL STIMULATION ASSAYS, ANTIGEN-SPECIFIC CELL ISOLATION), AND PERFORMANCE OF B ASSAYS FOR THE CONSORTIUM. IN ADDITION, WE WILL CONDUCT SINGLE CELL EXPERIMENTS USING THE 1OX GENOMICS CHROMIUM PLATFORM FOR B CELL IMMUNE PROFILING AND GENE EXPRESSION SINGLE CELL RNASEQ TO INVESTIGATE THE HBV-SPECIFIC ANTIBODY AND B CELL RESPONSES. DR MANSUN LAW WILL COMMUNICATE REGULARLY WITH THE HARVARD PL DR GEORG LAUER VIA EMAIL, PHONE AND ZOOM CALLS, ATTEND SCIENTIFIC MEETINGS AND DISCUSSION OF THE CONSORTIUM, AND ASSIST WITH DR LAUER IN THE PREPARATION OF SCIENTIFIC MANUSCRIPTS AND NIH REPORTS.
Scripps Research Institute
Project Grant R01AI184931
$420.4k 7/31/24 245795S
IN THIS COLLABORATIVE PROJECT, MY LAB WILL PERFORM THE FOLLOWING ACTIVITIES: Â ¢ IMPLEMENT COMPUTATIONAL METHODS FOR SINGLE CELL RNA-SEQ (SCRNA-SEQ) ANALYSIS. Â ¢ USE UNSUPERVISED CLUSTERING ALGORITHM TO IDENTIFY CELL SUBSETS IN THE SCRNA-SEQ DATA. Â ¢ USE NS-FOREST TO IDENTIFY CELL TYPE-SPECIFIC BIOMARKERS USING THE SCRNA-SEQ DATA. Â ¢ USE FR-MATCH TO STATISTICALLY COMPARE CELL TYPES ACROSS DIFFERENT STAGES OF THE DISEASE. Â ¢ PERFORM MULTI-ASSAY DATA INTEGRATION ANALYSIS USING DIABLO FOR THE EXPERIMENTAL AND CLINICAL DATA COLLECTED IN THE STUDY. Â ¢ USE SUPERVISED APPROACH BASED ON THE SGCCA TECHNIQUE TO DEVELOP A PREDICTIVE MODEL OF CHRONIC HBV INFECTION CLASSIFICATION USING THE IDENTIFIED PATIENT COHORTS. Â ¢ PARTICIPATE IN CONSORTIUM COMMUNICATIONS ON A REGULAR BASIS VIA MEETINGS, DISCUSSIONS, AND EMAILS. Â ¢ ASSIST DR. LAUER WITH THE PREPARATION OF SCIENTIFIC PUBLICATIONS AND NIH REPORTS.
J. Craig Venter Institute, Inc.
Project Grant R01AI184931
$68.5k 7/31/24 245795S
HEPATITIS B VIRUS (HBV) INFECTION REMAINS A MAJOR THREAT TO GLOBAL HEALTH, WHERE APPROXIMATELY 300 MILLION PERSONS WORLDWIDE ARE INFECTED. DUE TO ITS LONG-TERM MORBIDITY AND MORTALITY THROUGH VIRAL-RELATED CIRRHOSIS AND HEPATOCELLULAR CARCINOMA AN ESTIMATED 1 MILLION ANNUAL DEATHS OCCUR WORLDWIDE, DESPITE AVAILABILITY OF PROPHYLACTIC VACCINES. THEREFORE, THERAPIES CAPABLE OF PRODUCING AT LEAST FUNCTIONAL CURE FOR CHRONIC HBV ARE URGENTLY NEEDED. MAJOR IMPEDIMENTS TO CURE OF HBV ARE ITS LATENCY AND A FUNCTIONALLY IMPAIRED IMMUNE RESPONSE CHARACTERIZED BY HIGH LEVELS OF IMMUNE EXHAUSTION. ADULT ACUTE HBV INFECTION LEADS ALMOST UNIVERSALLY TO FULL CONTROL OF VIREMIA. THIS STATE OF FUNCTIONAL CURE IS ALSO ACHIEVED IN A SMALL MINORITY OF PATIENTS AFTER MANY YEARS OF CHRONIC HBV INFECTION. TYPICALLY, THE VIRUS IS NOT COMPLETELY ELIMINATED FROM THE HOST, BUT REMAINS PRESENT IN THE FORM OF CCCDNA WITH REPLICATION BEING SUPPRESSED BY HOST IMMUNITY, HENCE THE TERM FUNCTIONAL CURE. THUS, THESE TWO GROUPS OF PATIENTS REPRESENT THE GOLD STANDARD FOR FUNCTIONAL CURE OF HBV INFECTION THAT IS THE GOAL OF MOST NOVEL THERAPY STRATEGIES. THERE IS STRONG EVIDENCE THAT HBV-SPECIFIC CD8 AND CD4 T CELLS ARE KEY TO BOTH ACUTE, BUT ALSO LONG-TERM CONTROL OF HBV. HOWEVER, HBV-SPECIFIC CD4 T CELL RESPONSES HAVE NOT BEEN ANALYZED IN GREAT DETAIL TO DATE. NEW REAGENTS ALLOWING DETAILED ANALYSIS OF HBV-SPECIFIC CD4 T CELL RESPONSES HAVE BEEN DEVELOPED BY OUR COLLABORATORS AT MGH AND WILL BE USED TO CHARACTERIZE THE KEY FEATURES OF PROTECTIVE CD4 IMMUNITY THAT ARE REQUIRED FOR FUNCTIONAL CURE. SIMILARLY, BCELLS AND THE ANTIBODIES THEY PRODUCE ARE IMPORTANT MEDIATORS OF HBV CONTROL, BUT THE EXPLORATION OF HOW THEY ARE IMPAIRED BY THE VIRUS AND HOW THEY CAN EXERT CONTROL REMAIN ILL-DEFINED. A BETTER UNDERSTANDING OF BOTH HBV-SPECIFIC CD4 T CELLS AND B CELLS AND HOW THEY INTERACT IS CRITICAL FOR THE RATIONAL DEVELOPMENT OF THERAPIES LEADING TO FUNCTIONAL CURE. TO ACHIEVE THIS GOAL, REPOSITORIES OF LARGE AMOUNTS OF PBMC FROM WELLDEFINED HBV POSITIVE COHORTS ARE INDISPENSABLE. THE VIRAL HEPATITIS AMBULATORY AT FIOCRUZ, RIO DE JANEIRO, BRAZIL REGISTERS AT LEAST 1000 CHRONIC AND 750 ACUTE CASES OF HBV INFECTION SINCE 1997. AMONG THOSE WITH CHRONIC HBV INFECTION WITH COMPLETE LABORATORY DATA, 65% HAD HBEAG NEGATIVE INFECTION, 16% HBEAG NEGATIVE HEPATITIS, 15% HBEAG POSITIVE HEPATITIS AND 5% HBEAG POSITIVE INFECTION. SINCE 2011 THE CLINIC HAS BEEN A REFERRAL SITE FOR ACUTE VIRAL HEPATITIS AND SINCE 2017 FOR PREGNANT WOMEN WITH VIRAL HEPATITIS. WE HAVE RECENTLY STARTED TO RECRUIT HBV-POSITIVE PATIENTS FOR BLOOD DRAWS USED TO EXTRACT PBMC AND PLASMA. SO FAR, 109 HBV-INFECTED INDIVIDUALS WERE ENROLLED, 95 WITH ACUTE HBV INFECTION AND 14 CHRONIC (8 HBEAG+ HEPATITIS, 6 HBEAG- HEPATITIS), IN WHICH A HIGH YIELD OF SEQUENTIAL AND SERIAL BANK SPECIMENS HAS BEEN STORED AND IS ALREADY AVAILABLE FOR DIVERSE IMMUNOLOGICAL ASSAYS. PROSPECTIVELY, WE PROPOSE TO PERFORM LARGE VOLUME BLOOD DRAWS IN BETWEEN 25 TO 30 PATIENTS EACH WITHIN THE FOLLOWING HBV PATIENT CATEGORIES: 1) FUNCTIONAL CURE FOLLOWING ACUTE HBV INFECTION; 2) FUNCTIONAL CURE IN CHRONICALLY HBV-INFECTED INDIVIDUALS WITH OR WITHOUT ANTIVIRAL TREATMENT; 3) CHRONIC HBEAG POSITIVE INFECTION; 4) CHRONIC HBEAG POSITIVE HEPATITIS; 5) CHRONIC HBEAG NEGATIVE INFECTION; AND 6) CHRONIC HBEAG NEGATIVE HEPATITIS. WE WILL ALSO HAVE LONGITUDINAL SAMPLING FOR THE FOLLOWING GROUPS, IN ORDER TO ANALYZE CHANGES IN IMMUNITY ASSOCIATED WITH CHANGING VIRAL REPLICATION: 1) ACUTE VIREMIC HBV INFECTION BEFORE FUNCTIONAL CURE 2) PATIENTS WITH HBEAG POSITIVE OR NEGATIVE HEPATITIS ONE YEAR AFTER INITIATION OF ANTIVIRAL THERAPY. WE EXPECT TO RECRUIT EACH YEAR AT LEAST 5 INDIVIDUALS WITH ACUTE HBV INFECTION AND 10 INDIVIDUALS EACH WITH CHRONIC INFECTION OR HEPATITIS, RESPECTIVELY. THIS STUDY WILL ALLOW TO DEFINE THE CD4 AND B CELL MEDIATED IMMUNE RESPONSE CHARACTERISTIC FOR DIFFERENT DISEASE STAGES ASSOCIATED WITH DIFFERENT LEVELS OF VIRAL CONTROL
Fundacao Oswaldo Cruz
Project Grant R01AI184931
$144.2k 7/31/24