Elucidating transcriptional control of interferon signaling
Active Project Grant Awarded Last action
- Award ID
- F31AI200352
- Recipient
-
University Of Utah UEI LL8GLEVH6MG3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $77,108
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- Salt Lake City, UT 84112, USA
Award details come from USAspending.gov.
Description
- Abstract
- Innate immune responses are the frontline detection and defense against invading pathogens. These responses include pathogen recognition receptors and downstream signaling pathways, which trigger signaling cascades upon detection of pathogen-associated molecular patterns. One such pathway is the cyclic GMP-AMP synthase- stimulator of interferon genes (cgas-sting) pathway, which detects double-stranded DNA in the cytoplasm. Activation of sting leads to a phosphorylation cascade involving the transcription factor IRF3, which leads to changes in the expression of hundreds of genes, including upregulating type i interferons and interferon- stimulated genes. Importantly, innate immune response pathways must strike a delicate balance to remain prepared to respond rapidly to pathogens. At the same time, IT prevents erroneous signaling that can lead to cancer and autoimmunity. Thus, these pathways are under tight regulatory control. However, the mechanisms that regulate innate immune responses downstream of cgas-sting are not fully understood. This proposal seeks to identify proximal regulators of the sting-IRF3-ifnβ signaling axis. Our preliminary data from a genome-wide crispr-CAS9 knockout screen in human monocytic cells identify the gene spen as a novel negative regulator of the sting-IRF3-IFN signaling axis. Spen was initially identified as a regulator of neural axon development in drosophila melanogaster. In recent years, spen has been found to act in other pathways, such as x-chromosome inactivation (XCI) and the notch signaling pathway. In these pathways, spen recruits ncor/SMRT1 and HDAC3, which act to modify chromatin and repress gene expression. Interestingly, spen has no known role in regulating type i IFN signaling. Spen has been labeled as a tumor suppressor gene, and several mutations and truncations of spen have been linked to cancers, including splenic marginal zone lymphoma and diffuse large b-cell lymphoma. Our preliminary data show that when spen is knocked out, the expression of interferon and interferon-stimulated genes increases at the mrna and protein levels. Bulk RNA sequencing data also confirms that spen is a negative regulator of interferon-stimulated genes, suggesting transcriptional dysregulation of IFN. The experiments outlined in this proposal will provide a greater understanding of how spen regulates innate immune signaling. With this proposal, we aim to 1) determine how spen regulates signaling via sting-IRF3-ifnb, 2) determine whether spen's regulatory role is unique to the cgas-sting pathway, and 3) investigate the cell-type-specific roles of spen. We seek to gain mechanistic insight into transcriptional regulation of innate immune responses, which could lead to knowledge and new treatments critical to treating viral infections, cancer, and autoimmunity.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $38,554 | |
| Amendment | $0 | |
| Original award | $38,554 |
Quick answers
Who received award F31AI200352?
F31AI200352 was awarded to University Of Utah by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 18, 2026.
How much is award F31AI200352 worth?
$77,108 has been obligated on F31AI200352.
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