Impact of viral RNA G-quadruplex unwinding by DHX36 on immune recognition by RIG-I and PKR
Active Project Grant Awarded Last action
- Award ID
- F31AI200274
- Recipient
-
University Of Missouri System UEI SZPJL5ZRCLF4
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $71,768
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- Columbia, MO 65211, USA
Award details come from USAspending.gov.
Description
- Abstract
- Viral infections are an area of significant concern to human health. The current anti-viral options for treatment of infected individuals are limited, often virus specific, and in many cases are resisted by viruses due to their high mutation rates. Therefore, there is a current need for anti-viral drugs that are broadly acting and target conserved viral elements that are difficult to mutate against. G-quadruplexes are unique structures that form in G-rich nucleic acid sequences that function as dynamic control elements for multiple functions critical to viral fitness, including transcription, translation, and transcript turnover. Recent advances in predictive software indicate that G- quadruplexes are conserved in the genomes of many pathogenic viruses, including influenza, HIV, and herpesviruses. Further literature experimentally supports the crucial functions of these structures and the protective anti-viral effect of targeting these molecules with small molecules drugs and anti-sense oligonucleotides. Additional research into how G-quadruplexes influence host-virus interactions, particularly in the immune system, will support the further development of treatments targeting these structures and could lead to promising immunomodulatory anti-virals. G-quadruplexes may represent a strategy to avoid host recognition by sterically hindering recognition motifs or downstream signaling interactions for RNA sensing proteins, like RIG-I and PKR, that can be circumvented by host G-quadruplex unwinding proteins (such as DHX36, a well- studied helicase known to interact with RIG-I and PKR) or targeting by G-quadruplex destabilizing drugs. A long- term goal of this proposal is to support the study of G-quadruplexes as a novel determinant of immune sensing and support the development of G-quadruplex targeting drugs as an avenue towards broad-spectrum anti-viral therapeutics. Specifically, the aims are 1) determine the influence of G-quadruplexes on immune sensing by RIG-I and PKR and 2) determine the influence of the G-quadruplex unwinding protein DHX36 on the immunogenicity of viral RNA that contains G-quadruplexes. To accomplish these aims, these RNA/protein interactions will be studied through both biochemical and cellular methods to obtain clear proof of interactions while also testing for biological significance. RNA from multiple pathogenic viruses will be used to rigorously test these interactions, driven by natural boundaries that preserve native structure. G-quadruplexes will be modulated with small molecules and controlled for with mutated sequences. Interactions will be measured through functionally mutated and truncated proteins, and the location on the RNA that these proteins interact with will be determined through chemical sequencing methods. The immunogenicity of G-quadruplex-containing RNA will be verified in immune reporter cells and derivative knockouts in multiple cell types to control cellular variability. In conclusion, these experiments will delineate the influence of G-quadruplexes in viral RNA on two critical RNA- sensing immune proteins and examine a potential host mechanism to counteract viral immune evasion.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $35,884 | |
| Amendment | $0 | |
| Original award | $35,884 |
Quick answers
Who received award F31AI200274?
F31AI200274 was awarded to University Of Missouri System by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 3, 2026.
How much is award F31AI200274 worth?
$71,768 has been obligated on F31AI200274.
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