Hepatic priming of CD4+ t cells directs effective hepatitis b virus immunity
Active Project Grant Awarded Last action
- Award ID
- F31DK135386
- Recipient
-
The Regents Of The University Of California. San Francisco UEI KMH5K9V7S518
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $379,740
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date 85% complete
- Place of performance
- San Francisco, CA 94143, USA
Award details come from USAspending.gov.
Description
- Abstract
- Chronic infection with hepatitis b virus (HBV) is a leading global cause of end-stage liver disease and hepatocellular carcinoma; fatal outcomes that can be prevented when serum hepatitis b surface antigen (hbsag) clearance is achieved, which rarely occurs with available treatments. Hbsag seroclearance is therefore the primary goal for next generation therapies. Whereas most adults who develop acute hepatitis b will clear hbsag and produce hbsag-specific antibodies (hbsab), most young children and neonates fail to clear hbsag and develop life-long infection. Most adults with chronic hepatitis b (CHB) therefore acquired infection in early life when the antiviral immune response proved ineffective. Understanding the immunologic differences responsible for the age gradient in hbsag seroclearance provides a roadmap for identifying therapeutic targets for redirecting the HBV immune response towards hbsag seroclearance. To achieve this objective, i will utilize both a well-established mouse model that recapitulates age-related serological outcomes observed in human HBV infections as well as already collected cytometry and single cell RNA sequencing (scrnaseq) data from an antiviral therapy withdrawal clinical trial. By employing these complementary sources of biological information in direct mouse-human comparison, i have the unique opportunity to make clinically relevant interrogations into the mechanisms of hepatic antigen presentation and the activation of CD4+ t cells by hepatic conventional dendritic cell (cdcs) that leads to hbsag seroclearance. These studies will also identify and test potential therapeutic targets that alter the hepatic immune priming environment to augment the rate of hbsag seroclearance in our mouse model. My proposal is composed of three specific aims. In specific aim 1 i will investigate the role of several CO- stimulatory signaling pathways to an age-dependent capacity of hepatic cdcs to activate CD4+ t cells in vitro. Also, i will use scrnaseq data to identify transcriptomic differences in antigen presenting cell populations that are associated with hbsag seroclearance in both mice and humans. In specific aim 2 i will use immunohistochemistry to image age-dependent immune cell interactions in hepatic tissues of mice and test whether these differences are indicative of age-dependent differences in t cell trafficking and organization in the liver parenchyma. Also, i will study CD4+ t cells from both mice and humans responding to HBV to again identify shared transcriptomic differences associated with hbsag seroclearance. Finally, in specific aim 3, i will attempt to rescue hbsag seroclearance by bypassing defects in CD4+ t cell priming or treating mice with agonistic antibodies that target t cell CO-stimulatory pathways identified in our preliminary investigations. By synergistically analyzing data from our mouse model and human clinical trial, my research aims to provide comprehensive insights into the intricate immune mechanisms influencing HBV seroclearance. By unraveling these complexities, i seek to identify promising therapeutic avenues that could pave the way for a clinical cure.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $47,767 | |
| Amendment | $47,767 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $47,203 | |
| Amendment | $47,203 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $45,923 | |
| Amendment | $45,923 | |
| Amendment | $45,923 | |
| Original award | $45,923 |
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Quick answers
Who received award F31DK135386?
F31DK135386 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on August 8, 2024.
How much is award F31DK135386 worth?
$379,740 has been obligated on F31DK135386.
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