Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses
Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses
批准号:
10553421
负责人:
JENNIFER A LUFF
金额:
$7.77万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-07-01 至 2023-06-30
关键词:
AddressAnimal ModelAnimalsAntiviral ResponseBindingBioinformaticsBiologyCanis familiarisCell Differentiation processCellsCutaneousDataDevelopmentFacultyFoundationsFunctional disorderGene ExpressionGenesGenetic DiseasesGoalsHIV InfectionsHealthHumanHuman PapillomavirusImmunocompromised HostImmunologic Deficiency SyndromesInfectionInfectious Skin DiseasesInterferonsInvestigationMalignant neoplasm of cervix uteriMass Spectrum AnalysisMediatingMentorsMucous MembraneOncogenesOrgan TransplantationPapillomavirusPapillomavirus InfectionsPatientsPersonsProteomicsRegulationRepressionResearchScientistSkin CarcinomaSumTestingVirus DiseasesWorkcanine modelcell typehuman diseaseinducible gene expressionkeratinocytenew therapeutic targetnovel therapeuticsresponseskillstherapeutic targettreatment responsetumorvirtual
中文摘要
项目摘要/摘要
英文摘要
Project Summary/ Abstract
Papillomavirus (PV) infections significantly impact human health. Mucosal PVs cause virtually all cases
of human cervical cancer, while cutaneous PVs cause severe skin infections and non-melanoma skin cancers
in patients with immunodeficiencies resulting from e.g. HIV infection, organ transplants, or genetic disorders.
Treatments for cutaneous PVs are limited and often ineffective. Thus, there is a critical need for development
of novel therapeutics directed at keratinocytes, the target cell of PV infections. Keratinocytes have the potential
to mount an antiviral response. Viral infection activates interferon regulator factors (IRFs), which upregulate
interferons (IFN) and IFN-stimulated antiviral genes. IRFs and IFNs are also tumor-suppressing, making them
particularly attractive as therapeutic targets for PV infections. However, both mucosal and cutaneous PVs can
repress IRF function and IFN expression. This repression is mediated by the E6 and E7 oncogenes of mucosal
PVs. While limited studies suggest that mucosal and cutaneous PVs differ in their E6 and E7 functions and that
IRF regulation of the IFN response in keratinocytes differs from that in other cell types, there are many more
questions than answers. Like humans, cutaneous PV infections occur in dogs and are more prevalent in
immunodeficient animals. Thus, the dog offers a natural spontaneous animal model for investigation of
cutaneous PV infections and for testing novel therapeutics. Indeed, our preliminary data demonstrate that
canine cutaneous PV E6 and E7 differentially disrupt IFN and IFN-stimulated gene expression in canine
keratinocytes. The long-range goal of our work is to develop novel therapeutics targeting IRFs and the IFN
response for treatment of cutaneous PV infections in immunodeficient patients, using a canine model of PV
infection. We hypothesize here that E6 and E7 from cutaneous PVs enhance viral infection by inhibiting IRF
function in keratinocytes using mechanisms unique to cutaneous PVs. In Aim 1, we will inhibit expression of
IRFs to determine their impact on cutaneous PV infection and on constitutive and inducible expression of IFNs
and IFN-stimulated genes in keratinocytes. In Aims 2 and 3, we will determine the mechanisms for cutaneous
PV E6- and E7-mediated disruption of IFNs and IFN-stimulated gene expression in keratinocytes. Specifically,
we will use mass spectrometry to identify E6 and E7 binding partners that modulate IRF expression and/or
function, and then identify mechanisms for E6 and E7 effects on these binding partners. Using human PV and
keratinocytes will address the human disease; using canine PV and keratinocytes will advance the dog model.
Results will lay the foundation for development of novel therapeutics that would by-pass E6 and E7 deleterious
effects. The mentoring team includes faculty with extensive expertise in keratinocyte biology, IRF and IFN
biology in differentiated cells, PV biology, and mass spectrometry proteomics and bioinformatics. In sum, the
proposed research will address a critical issue in human and animal health, capitalize on the diverse skill sets
of the interdisciplinary mentoring team, and enhance my maturation as an independent clinician scientist.
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A subset of equine oral squamous cell carcinomas is associated with Equus caballus papillomavirus 2 infection.
马口腔鳞状细胞癌的一部分与马科乳头瘤病毒 2 型感染有关。
DOI:
10.1016/j.jcpa.2023.06.003
发表时间:
2023
期刊:
Journal of comparative pathology
影响因子:
0.8
作者:
[Luff,Jennifer, Weingart,Shaina, May,Susan, Murphy,Brian]
通讯作者:
Murphy,Brian
DOI:
10.3389/fvets.2021.570982
发表时间:
2021
期刊:
Frontiers in veterinary science
影响因子:
3.2
作者:
[Quinlan S, May S, Weeks R, Yuan H, Luff J]
通讯作者:
Luff J
DOI:
10.3390/ani11020491
发表时间:
2021-02-13
期刊:
Animals : an open access journal from MDPI
影响因子:
--
作者:
[Deming AC, Wellehan JFX, Colegrove KM, Hall A, Luff J, Lowenstine L, Duignan P, Cortés-Hinojosa G, Gulland FMD]
通讯作者:
Gulland FMD
Pathology in Practice.
病理学实践。
DOI:
10.2460/javma.21.01.0017
发表时间:
2022
期刊:
Journal of the American Veterinary Medical Association
影响因子:
--
作者:
[Hu,TriciaG, Dehghanpir,ShannonD, Sasaki,Emi, Costa,VictoriaR, Pucheu-Haston,CherieM, Piero,FabioDel, Withers,SitaS]
通讯作者:
Withers,SitaS
DOI:
10.1111/vde.13208
发表时间:
2023-10
期刊:
Veterinary dermatology
影响因子:
1.4
作者:
[Ana R Resendes;Karen E Trainor;Monali Bera;Ryan Chuang Fu Cheng;Jennifer Luff]
通讯作者:
Ana R Resendes;Karen E Trainor;Monali Bera;Ryan Chuang Fu Cheng;Jennifer Luff
共 9 条
The role of CIB1 on cutaneous papillomavirus replication and transcription
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批准号:10542410
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项目类别:
-
资助金额:$11.4万
-
财政年份:2022
-
负责人:JENNIFER A LUFF
-
依托单位:
The role of CIB1 on cutaneous papillomavirus replication and transcription
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批准号:10351161
-
项目类别:
-
资助金额:$11.4万
-
财政年份:2022
-
负责人:JENNIFER A LUFF
-
依托单位:
Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses
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批准号:9223772
-
项目类别:
-
资助金额:$12.93万
-
财政年份:2017
-
负责人:JENNIFER A LUFF
-
依托单位:
Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses
-
批准号:10217281
-
项目类别:
-
资助金额:$12.93万
-
财政年份:2017
-
负责人:JENNIFER A LUFF
-
依托单位:
海外基金