Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection
上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用
基本信息
- 批准号:10549310
- 负责人:
- 金额:$ 36.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-10 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAdenovirus InfectionsAdenovirus VectorAdenovirusesAdultAntiviral TherapyApicalAttenuatedAutophagocytosisBackBiologicalBiological ProcessCalmodulinCell AdhesionCell PolarityCell membraneCell modelCellsCellular StressChronic lung diseaseClathrin AdaptorsClinicalCyclic AMP-Dependent Protein KinasesCytoskeletonDataDevelopmentDiseaseDockingEndoplasmic ReticulumEndosomesEpidermal Growth Factor ReceptorEpithelial CellsEpitheliumExhibitsExposure toFailureFutureGAB1 geneGenesGenetic TranscriptionGoalsHumanImmuneImmune responseImmune signalingIndividualInfectious AgentInflammatoryInnate Immune ResponseInnate Immune SystemInvadedKnowledgeLeadLigandsLinkLung infectionsMalignant NeoplasmsMammalian CellMedicalMembraneMembrane ProteinsModelingMolecularMolecular ConformationMultivesicular BodyNatural ImmunityOncolyticPathogenesisPathologicPathway interactionsPhysiologicalPlayProcessProtein SortingsProteinsReceptor SignalingRecombinantsRecyclingResearchRespiratory DiseaseRespiratory SystemRespiratory Tract InfectionsRoleSerotypingSignal PathwaySignal TransductionSortingStimulusStressSurfaceTNF geneTestingTherapeuticTherapeutic InterventionTissuesTransplant RecipientsVirusairway epitheliumairway immune responseapical membranebasolateral membranebeta cateninbiological adaptation to stresscytokinedesignendosome membraneezringene productgene therapy clinical trialhuman diseaseinnate immune functioninsightnew therapeutic targetnovelnovel therapeuticspathogenprotein activationpublic health relevancereceptorreceptor expressionreceptor functionrelease of sequestered calcium ion into cytoplasmrespiratoryresponsesrc-Family Kinasestraffickingtranscytosis
项目摘要
ABSTRACT
The apical surface of polarized epithelium constitutes one of the first points of contact between the host and
pathogens such as human adenoviruses (HAdVs) that invade the lumen of the respiratory tract. In recent
years, it has become clear that respiratory epithelial cells not only serve as functional and physical barriers, but
actively contribute to the innate immune system providing initial protection against external pathogens. The
EGF receptor (EGFR), which typically exhibits basolateral polarity, has emerged as a key player in the innate
immunity of respiratory epithelium to a variety of infectious and noninfectious noxious stimuli. In contrast to the
canonical ligand-stimulated EGFR pathway, a number of cellular stresses including HAdV infection (our
studies) trigger an alternative mode of EGFR trafficking associated with sustained EGFR activity in non-
degradative endosomes. However, molecular mechanisms regulating this pathway remain poorly understood.
In addition, despite significant progress in understanding the pathological and therapeutic stresses that activate
it, relatively little is known about EGFR function in the context of cellular stress. We have recently found that
stress-induced EGFR signaling is involved in innate immune responses triggered by HAdV cell entry, as well
as following exposure to the pro-inflammatory cytokine TNF-α, in respiratory epithelial cells. Moreover, HAdV
encodes an early gene product that suppresses this pathway by promoting EGFR degradation, and which
could provide new insights to potential targets for future anti-viral therapies. Interestingly, our preliminary
studies have revealed that EGFR stress responses were tightly regulated by epithelial cell polarity, with robust
stress-induced EGFR responses only observed when receptors were mistargeted to apical membranes. In
addition, HAdV co-opted cellular pathways contributing to innate immune signaling by enabling dynamic EGFR
membrane remodeling associated with enhanced stress-induced EGFR signaling from apical membranes.
The newly described EGFR innate immune system is likely to have a central role in protecting the lung from
infection with HAdVs and perhaps other pathogens. Conversely, failure to curb this signaling network may lead
to tissue damage, respiratory compromise, and potentially systemic HAdV infections. Our research plan will
identify novel mechanisms regulating dynamic EGFR membrane remodeling in polarized epithelial cells (Aim
1), and stress-induced EGFR innate immune signaling from endosomes (Aim 2); and analyze EGFR innate
immune signaling pathways that are activated as a consequence of HAdV infection in primary human
respiratory epithelial cells and new physiological cells models with enhanced apical EGFR expression (Aim 3).
Although our studies will be carried out in the context of HAdVs, successful completion of this project will have
a broad impact on a variety of respiratory conditions in need of new therapies.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CATHLEEN R CARLIN其他文献
CATHLEEN R CARLIN的其他文献
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{{ truncateString('CATHLEEN R CARLIN', 18)}}的其他基金
Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection
上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用
- 批准号:
10209611 - 财政年份:2021
- 资助金额:
$ 36.83万 - 项目类别:
Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection
上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用
- 批准号:
10368996 - 财政年份:2021
- 资助金额:
$ 36.83万 - 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
- 批准号:
7995957 - 财政年份:2008
- 资助金额:
$ 36.83万 - 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
- 批准号:
8197511 - 财政年份:2008
- 资助金额:
$ 36.83万 - 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
- 批准号:
7741208 - 财政年份:2008
- 资助金额:
$ 36.83万 - 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
- 批准号:
6654464 - 财政年份:2002
- 资助金额:
$ 36.83万 - 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
- 批准号:
6544872 - 财政年份:2002
- 资助金额:
$ 36.83万 - 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
- 批准号:
6945125 - 财政年份:2002
- 资助金额:
$ 36.83万 - 项目类别:
MECHANISMS OF ABERRANT EGF RECEPTOR SORTING IN POLYCYSTIC KIDNEY DISEASE
多囊肾疾病中异常 EGF 受体分选的机制
- 批准号:
6651773 - 财政年份:2002
- 资助金额:
$ 36.83万 - 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
- 批准号:
6794606 - 财政年份:2002
- 资助金额:
$ 36.83万 - 项目类别:
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