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C/EBPβ Regulation of the Type 1 IFN Response; Sensitizing Keratinocytes to Direct Activators of Cytosolic PRRs and DNA Damage-Induced Cell Death

Award Number: R01AR081974
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cellular stress, DNA damage, pathogen insult, and immune mechanisms can activate molecular pathways that result in regulated cell death. Increasing our understanding of the pathways that regulate cell death decisions in response to cellular stress is critical as misregulated cell death is linked to cancer, neurodegeneration and autoimmune diseases. The epidermis is the first line of defense to cutaneous microbes, viruses and environmental insults, and keratinocytes play a critical role in the host innate immune response mediated by type I interferons (IFN-I). In addition to anti-microbial and anti-viral responses this same IFN-I response also mediates diverse cellular and biological responses such as proliferation, apoptosis, senescence and the DNA damage response. Recent data from out laboratory suggest that the CCAAT/enhancer-binding protein-β (C/EBPβ) transcription factor is a novel regulator the keratinocyte type IFN-I response. We observed the conditional deletion of C/EBPβ in mouse epidermis (CKOβ) resulted in increased expression of IFNb and numerous ISGs which included cytosolic pattern recognition receptors (cPRRs). cPRRs sense viral/pathogen RNA and DNA as well as damaged host cytosolic DNA and RNA to trigger a IFN-I response. CKOβ keratinocytes treated with direct activators of cytosolic PRRs displayed a greatly increased IFN-I response that surprisingly resulted in increased apoptosis via the activation of caspase-8 and caspase-3. As breifly mentioned, DNA damage can activate the innate immune response. DNA damaging agents can result in modifications and structural changes in RNA and DNA that could potentially be sensed by cytosolic PRRs. We observed that CKOβ keratinocytes challenged with DNA damage displayed increase caspase 8-mediated apoptosis that was dependent on the interferon a/b receptor (INFAR). Activation of a type IFN-I response can result in the increased expression of ISGs with apoptotic functions that activate caspase-8 mediated apoptosis via death receptor signaling. The objective of this proposal is to understand molecular basis for how C/EBPβ negatively regulates the IFN-I response and caspase-8 mediated apoptosis in response to direct activators of cytosolic PRRs and DNA damage in vivo in mouse epidermis and in primary keratinocytes. We hypothesize that C/EBPβ negatively regulates the IFN-I response in keratinocytes and the loss of C/EBPβ sensitizes keratinocytes to the direct activation of cytosolic PRRs by pathogen RNA/DNA or damaged host RNA/DNA to induce pro-apoptotic ISGs and caspase 8-mediated apoptosis. These experiments will increase our understanding of a novel pathway by which C/EBPβ regulates activation of cPRRs and the IFN-I response to control cell death decisions in response to cellular stress including DNA damage. This increased understanding could identify new therapeutic targets to restore proper regulation of cell death to treat skin cancer, skin infectious diseases, and skin autoimmune diseases.


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: 2024 ( Subtotal = $310,799 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/9/2024	NON-COMPETING CONTINUATION	$310,799
														Subtotal = $310,799

Issue Date FY: 2023 ( Subtotal = $320,411 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/11/2023	NEW	$320,411
														Subtotal = $320,411

Grand Total All Awards = $631,210

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C/EBPβ Regulation of the Type 1 IFN Response; Sensitizing Keratinocytes to Direct Activators of Cytosolic PRRs and DNA Damage-Induced Cell Death

Award Number: R01AR081974

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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