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Understanding the Structural Basis of PKR Activation by Interferon Gamma RNA

Award Number: F31AI200294
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Understanding the Structural Basis of PKR Activation by Interferon Gamma RNA - Project Summary/Abstract Interferon gamma (IFN-γ) is a cytokine that plays a critical role in protective immunity by activating numerous downstream signaling cascades. Due to its important role, IFN-γ expression is tightly regulated to prevent uncontrolled activation and inflammatory signaling. Previous research revealed that IFN-γ mRNA controls its own translation through a unique autoregulatory cycle where the IFN-γ mRNA folds into a structure that activates protein kinase R (PKR). Activated PKR dimers phosphorylate eukaryotic initiation factor 2α (eIF2α), which subsequently suppresses IFN-γ translation. When PKR activation is reduced, the IFN-γ mRNA can be translated and the resulting IFN-γ protein upregulates PKR expression to maintain this finely tuned cycle. Dysregulation of these pathways has been linked to the progression of various autoimmune or neurodegenerative diseases. The IFN-γ mRNA forms a large pseudoknot-containing structure comprised of the 5' UTR and first 26 translated codons. Since the structure extends into the coding region, the mRNA is proposed to dynamically refold between conformations, accommodating a dual function as a PKR activator and translation template. While secondary structures of the alternate conformations have been proposed, there is limited knowledge about the 3D structures and their involvement in regulating IFN-γ expression. This project will integrate structural biology and biochemical approaches to characterize the IFN-γ mRNA conformational dynamics and elucidate the molecular basis of PKR activation. The first aim will employ cryo-EM and functional assays to characterize these distinct IFN-γ mRNA conformational states, and the second aim will establish the link between these conformations and PKR activation by capturing the structure of the IFN-γ-PKR complex. This research will examine the structural basis for IFN-γ mRNA's dual regulatory functions and advance the understanding of how conformational dynamics enable precise control of gene expression. Since IFN-γ overproduction and PKR dysregulation drive multiple disease states, these mechanistic insights may unveil opportunities for new RNA-targeted therapies. This project will be conducted in the Toor lab at UCSD, which provides a collaborative and innovative environment with access to many resources for physical and intellectual support. In addition to technical skills, the training plan will incorporate additional experiences for professional growth in scientific communication and mentorship. The combination of these efforts will provide the optimal foundation for cultivating the expertise needed for success as an independent researcher in RNA-based therapeutic discovery.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,714 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	5/27/2026	NEW	$0
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	5/27/2026	NEW	$43,714
														Subtotal = $43,714

Grand Total All Awards = $43,714

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Understanding the Structural Basis of PKR Activation by Interferon Gamma RNA

Award Number: F31AI200294

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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