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Genomic regulation of immune response by a STAT1 gain of function mutation

Award Number: R00AI177758
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Genomic regulation of immune response by a STAT1 gain of function mutation - Project Summary/Abstract The coordinated effort of the immune system in host defense is dependent upon the proper release and interpretation of different cytokine signals. Several examples of monogenic diseases targeting the JAK-STAT pathway reveal there is still a critical need to understand basic principles of cytokine signaling and cytokine output. For example, patients with STAT1 gain-of-function (GOF) mutations exhibit a type 1/IFN-gamma bias that antagonizes a type 3/IL-17 immune response important for controlling fungal infection, yet patients also, paradoxically, exhibit chronic and sometimes lethal viral infections. Using a novel conditional knock in STAT1- GOF mouse model, we demonstrate that STAT1-GOF mice exhibit an impaired NK and CD8 T cell effector response and develop a cytokine storm with viral infection. This is due to an impaired tissue-specific and microbiome-dependent deficit in IFN-gamma production by liver NK cells, ILC1s, and iNKT cells early during infection. Continuing with these studies, the goal of this application is to understand how perturbations in cytokine signaling have downstream and long-term effects in immune response. This proposal tests the hypothesis that prior exposure to cytokine stimuli have long-term effects on gene expression and immune cell function. The approach is divided into three specific aims: first, to determine the epigenetic mechanisms underlying how a STAT1-GOF mutation alters transcriptional output; second, elucidate the mechanism underlying the tissue-specific reduction of IFN-gamma in STAT1-GOF mice with viral infection; and three, to determine the consequences of a cytokine storm on CD8 T cell memory. During the mentored phase of the K99, the candidate will be trained in various genomic sequencing technologies and bioinformatic analysis to investigate AIM 1. Alongside research training, the candidate will participate in career development courses and workshops about grant writing, laboratory management, and teaching to fulfill her goal to attain a tenure- track independent research position. The training phase will be in Dr. John O’Shea’s laboratory in NIAMS at the NIH, supported by excellent resources, expertise in the laboratory, and vibrant NIH research community. These studies and career development plan will launch the R00 phase of independent research to investigate AIM 2 and AIM 3. The broader implication of this work is it will uncover basic cytokine signaling mechanisms broadly applicable to the field of immunology and identify potential therapeutic options for patients with altered set points.


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 = $249,000 )
2026	2026	REDACTED DUE TO PII		COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	3/27/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Genomic regulation of immune response by a STAT1 gain of function mutation

Award Number: R00AI177758

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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