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Cytosolic DNA sensing pathway regulation via non-canonical NF-kB signaling

Award Number: R01AI190082
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: 04/10/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Cytosolic DNA sensing pathway regulation via non-canonical NF-kB signaling - Project Summary The induction of a host type I interferon (IFN-I) response is classically understood to play an essential role in combatting virus infections. Detection of microbial nucleic acids in the cytosol by pattern recognition receptors (PRRs) triggers a signal transduction cascade that culminates in the activation of the IFN-I response. Emerging studies have linked previously unknown roles for cytosolic DNA sensing PRRs in detecting aberrant DNA species of self-origin to trigger the onset of age-related diseases, neurological disorders, and autoinflammatory conditions. Thus, there is a critical need to delineate the mechanisms by which cytosolic DNA sensing PRRs control IFN-I activation to develop the next generation of therapeutics to treat viral infections and DNA damage driven inflammatory disease states. We have recently identified a novel cross-talk phenomenon between cytosolic DNA sensing PRRs and the non-canonical NF-κB signaling pathway. While the non-canonical NF-κB pathway primarily governs lymphoid organogenesis and B-cell survival and maintenance in response to extracellular ligation of select members of the TNF receptor superfamily, our data unexpectedly revealed that intracellular ligation of cytosolic DNA sensing PRRs also triggered non-canonical NF-κB signaling. Furthermore, non-canonical NF-ĸB pathway activation amplified the IFN-I response during cytosolic DNA sensing PRR stimulation. Further investigation revealed the central regulator of the non-canonical NF-ĸB pathway, NIK was critical in enhancing cytosolic DNA dependent activation of IFN-I, but surprisingly, did not require its signaling partner, IKKα, nor downstream non-canonical NF-ĸB signal transduction. Instead, we found NIK interacted with and activated STING, an essential signaling adaptor required for IFN-I activation downstream of cytosolic DNA sensing PRRs. The mechanisms by which NIK elicits STING signaling is incompletely defined while induction of NIK/non-canonical NF-ĸB signaling in the cytosolic DNA sensing pathway is unknown. Regulatory factors that control NIK signaling during cytosolic DNA sensing also remain poorly understood. The central hypothesis of this proposal is that the non-canonical NF-ĸB pathway activator, NIK, is induced via a previously unknown mechanism during cytosolic DNA sensing and upon stabilization, exerts an additional layer of control on IFN-I activation in the cytosolic DNA signaling pathway by supporting STING signal transduction events. Interrogating protein-protein interaction network datasets, we identified novel regulators of NIK-STING signaling and propose to investigate their contributions in our specific aims: (Aim 1) Determine how NIK/non-canonical NF-ĸB is activated upon cytosolic DNA sensing. (Aim 2) Decipher the mechanisms by which NIK engages STING signaling. We anticipate our studies will broadly impact both the STING biology and non-canonical NF-κB signal transduction fields and will shed new light into developing new therapeutic strategies in combating DNA driven inflammatory disease states.


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 = $372,997 )
2026	2026	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	1	4/10/2026	NEW	$372,997
														Subtotal = $372,997

Grand Total All Awards = $372,997

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Cytosolic DNA sensing pathway regulation via non-canonical NF-kB signaling

Award Number: R01AI190082

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: 04/10/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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