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All Federal Grant Awards
Project Grant F32AI126703
Award Date
3/1/17
Completion Date
6/30/19
Dollars Obligated
$133K
Overview
Activity
8
Transactions
8
Subawards
Similar Awards
Federal Agency
National Institute of Allergy and Infectious Diseases
Awardee
Seattle Biomedical Research Institute (RFSAGXAA3LG3)
Federal Grant Program
93.855
Assistance Type
Project Grant
Place of Performance
Seattle, WA 98109, USA
Update #1
Update #2
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION
Posted 1/16/17
5
1
2
Mod #
Description
ReasonForModification
Federal Obligation
Date
Not listed
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION - PROJECT SUMMARY MYCOBACTERIUM TUBERCULOSIS (MTB), THE CAUSATIVE AGENT OF TUBERCULOSIS (TB), INFECTS ONE THIRD OF THE WORLD'S POPULATION AND KILLS OVER A MILLION PEOPLE ANNUALLY. ALTHOUGH IT IS KNOWN THAT CD4 T CELLS AND INTERFERON (IFN) ARE CRUCIAL FOR DEFENSE AGAINST MTB, A GENERAL LACK OF UNDERSTANDING OF HOW THIS RESPONSE IS REGULATED HAS THUS FAR HAMPERED SUCCESSFUL VACCINE DEVELOPMENT. OUR LAB FOCUSES ON THE CD4 T CELL RESPONSE TO TWO IMMUNODOMINANT MTB ANTIGENS: ESAT6, WHICH IS EXPRESSED CONTINUOUSLY, AND AG85B, WHICH IS EXPRESSED ONLY DURING BACTERIAL REPLICATION. WE HAVE FOUND THAT DIFFERENTIAL EXPOSURE OF THESE T CELLS TO THEIR COGNATE ANTIGENS IN THE LUNG RESULTS IN FUNCTIONAL EXHAUSTION OF ESAT6-SPECIFIC T CELLS BUT NOT AG85B-SPECIFIC T CELLS. AN UNBIASED BIOINFORMATICS APPROACH PREDICTED VITAMIN D RECEPTOR (VDR) AS A REGULATOR OF A SUBSET OF GENES THAT ARE ENRICHED IN AG85B-SPECIFIC T CELLS, LEADING US TO INVESTIGATE THE ROLE OF T CELL VDR SIGNALING DURING MTB INFECTION. INDEED, VDR DEFICIENCY HAD DIFFERENTIAL EFFECTS ON MTB-SPECIFIC CD4 T CELLS IN AN IN VIVO MOUSE INFECTION MODEL: ESAT6-SPECIFIC T CELLS FAILED TO EXPAND, YET AG85B-SPECIFIC T CELLS HAD ENHANCED IFN PRODUCTION. THESE RESULTS HAVE INTERESTING IMPLICATIONS FOR MTB THERAPEUTICS BECAUSE LOW VITAMIN D LEVELS HAVE LONG BEEN ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO DISEASE, ALTHOUGH THE ROLE OF VITAMIN D SIGNALING IN T CELLS HAS NEVER BEEN EXPLORED IN THE CONTEXT OF TUBERCULOSIS. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT VDR SIGNALING IN BOTH T CELLS AND MACROPHAGES PLAYS AN ESSENTIAL ROLE IN PROTECTION FROM TUBERCULOSIS. THIS HYPOTHESIS WILL BE TESTED USING A COMBINATION OF SYSTEMS BIOLOGY AND CELLULAR IMMUNOLOGY APPROACHES. MORE SPECIFICALLY, AIM 1 WILL SEEK TO IDENTIFY VDR TARGET GENES OF ESAT6- AND AG85B-SPECIFIC T CELLS BY COMPARISON OF WT AND VDR-/- T CELL TRANSCRIPTOMES USING RNA-SEQ. AIM 2 WILL ADDRESS THE QUESTION OF HOW VDR IS CONTROLLING THE MAINTENANCE OF MTB-SPECIFIC T CELLS AND WHETHER IT IS INDEED DEPENDENT ON ANTIGEN AVAILABILITY. FINALLY, AIM 3 WILL USE T CELL-SPECIFIC VDR KNOCKOUT MICE AND MIXED BONE MARROW CHIMERAS TO SIMULTANEOUSLY ASSESS THE CONTRIBUTIONS OF MYELOID CELLS AND T CELLS TO VITAMIN D-MEDIATED PROTECTION. COMBINED, THE STUDIES PROPOSED HERE WILL REVEAL THE MOLECULAR NETWORKS TARGETED BY VITAMIN D AND ELUCIDATE HOW T CELL VDR SIGNALING INFLUENCES THE OUTCOME OF MTB INFECTION.
($6k)
1/12/21
Not listed
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION
$21.9k
2/15/19
Not listed
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION
$30.1k
12/20/18
Not listed
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION
($30k)
12/20/18
Not listed
THE ROLE OF VITAMIN D RECEPTOR SIGNALING IN T CELLS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION
$1.0k
5/24/18