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Forkhead factor regulation in oral viral infection

Award Number: F30DE030666
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/15/2023

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Forkhead factor regulation in oral viral infection - The oral cavity is the initial site of infection for many pathogens, including viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that is shed in saliva, which is the primary route for spread between individuals. While in most cell types KSHV establishes a lifelong latent infection, in primary human gingival epithelial cells (HGEP) KSHV can establish a lytic infection, with sustained viral gene expression driven by the essential lytic viral factor replication and transcription activator (RTA). Importantly, lytic KSHV infection of oral epithelial cells leads to the production and release of new infectious virions, a key early step in KSHV infection that can lead to viral spread and chronic infection of other cell types in the human body. Despite the clinical and biological importance of oral infection as an initial step in KSHV infection, little is known about the host-pathogen interactions and their control mechanisms during KSHV infection of oral epithelial cells. Through genome-wide transcriptome analysis, one member of the forkhead box family of transcription factors (FOX TFs) was identified as rapidly and robustly induced upon de novo KSHV infection in HGEP cells. The FOX factors comprise a family TFs responsible for many cellular processes including cell growth and differentiation. However, little is known about the roles of FOX TFs in the context of viral infection. Preliminary data revealed that a large number of predicted target genes of the FOX TF are de-regulated during KSHV infection. Many of these targets encode key regulators of critical cellular functions. While the identified FOX TF is highly induced upon KSHV infection of oral cells, it is expressed at very low levels in uninfected oral cells, suggesting a rapid transcriptional switch driven by viral infection. The purpose of this project is to dissect the mechanism of FOX TF silencing in uninfected oral epithelial cells, and to determine how lytic viral infection disrupts this silencing, thereby promoting rapid alterations of normal cellular functions in infected oral epithelial cells. To examine repressive mechanisms in the oral cavity, Aim 1 focuses on identification of epigenetic enzymes that restrict FOX TF expression. It is hypothesized that viral factors disrupt the silencing of these host epigenetic enzymes during lytic infections. Aim 2 will identify how specific KSHV proteins induce the expression of FOX TF. A combination of genome-wide studies coupled with KSHV mutants will be used to analyze how KSHV infection affects FOX TF regulatory regions to result in FOX TF induction. In summary, this study will identify a novel viral mechanism in which the virus exploits a central host transcription factor to deregulate key cellular processes during lytic infection. The completion of this project will provide in-depth training in epigenetics, virology and genomics approaches. These skills will be enhanced in the outstanding research environment provided by the Comprehensive Training Program in Oral Biology at the University of Florida College of Dentistry, which incorporates tailored mentorship and excellent clinical and research training to prepare the applicant for a career as a clinician-scientist.


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 = -$3,778 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	2	3/22/2024	NON-COMPETING CONTINUATION	-$3,778
														Subtotal = -$3,778

Issue Date FY: 2023 ( Subtotal = -$3,294 )
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	2	5/4/2023	NON-COMPETING CONTINUATION	-$3,294
														Subtotal = -$3,294

Issue Date FY: 2022 ( Subtotal = $46,665 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	2	6/16/2022	NON-COMPETING CONTINUATION	$46,665
														Subtotal = $46,665

Issue Date FY: 2021 ( Subtotal = $44,575 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	1	2/2/2021	NEW	$0
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	1	1/27/2021	NEW	$44,059
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	002	1	6/17/2021	NEW	$516
														Subtotal = $44,575

Grand Total All Awards = $84,168

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Forkhead factor regulation in oral viral infection

Award Number: F30DE030666

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/15/2023

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