The Roles of Autophagy in Limbal/Corneal Epithelia.
自噬在角膜缘/角膜上皮中的作用。
基本信息
- 批准号:10400950
- 负责人:
- 金额:$ 48.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAgingAniridiaAnteriorAttenuatedAutophagocytosisBCL2 geneBasal CellBiochemicalBiologicalBiological ModelsBiologyCatabolic ProcessCell MaintenanceCell NucleusCell ProliferationCellsCellular AssayChemical BurnsClinicalComplementComprehensionConjunctival PterygiumConnexin 43CorneaCorneal DiseasesDefectDiabetes MellitusDiseaseEnvironmentEpithelialEpithelial CellsEtiologyExcisionEyeFamilyFilmFuchs&apos Endothelial DystrophyGenesGoalsHomeostasisHumanImpairmentInjuryInvestigationKeratinKeratopathyKnock-in MouseKnowledgeLabelLeadLightingLysosomesMaintenanceMeasuresMediatingMicroRNAsMicroscopyModalityModelingMolecularMonitorMucin 1 proteinMusNuclearOrganellesPatientsPharmacologyPhysiologicalPlasminogen Activator Inhibitor 2PlayProteinsReceptor Protein-Tyrosine KinasesRecurrenceRegulationReportingRestRoleSignal TransductionStarvationStevens-Johnson SyndromeStreamStressStructureSurfaceTechniquesTestingTissuesTransplantationVesicleYY1 Transcription Factorbasebiomarker evaluationclinical applicationcorneal epithelial wound healingcorneal epitheliumdiabeticdiabetic patientepithelial stem cellgain of functionimprovedin vivoinsightinvolucrinknock-downlimballoss of functionmouse modelnegative affectnotch proteinnovelnovel strategiesocular surfacepreservationresponsestemstem cell biomarkersstem cell homeostasisstem cell proliferationstem cellswoundwound healing
项目摘要
PROJECT SUMMARY/ABSTRACT
The anterior surface of the eye functions as a barrier to the external environment, protects the delicate
underlying structures from injury, supports a tear film and maintains transparency. These functions are
achieved, in part, through the corneal and limbal epithelia, which must maintain proper proliferation and
differentiation. Autophagy, a catabolic process by which cells adapt to intrinsic and extrinsic stress-related
situations, has been shown to also regulate proliferation and differentiation. Despite the many advances made
in our understanding of corneal and limbal epithelial biology, autophagy remains largely unstudied. We have
recently reported that: (i) under resting conditions, autophagy is greater in limbal epithelial basal compared with
corneal epithelial basal cells; (ii) autophagy contributes to limbal epithelial proliferative capacity; and (iii)
autophagy enables proper activation of transit amplifying (TA) cells following wounding. We also have
preliminary evidence that: (i) NUS1 is a novel upstream regulator of autophagy in the limbal epithelium; (ii)
blocking autophagy impairs corneal epithelial differentiation and the removal of nuclear material (nucelophagy);
and (iii) the receptor tyrosine kinase, EphA2, positively affects corneal epithelial differentiation via regulating
end stage autophagy. These observations lead us to hypothesize that autophagy is required to maintain limbal
epithelial stem and TA cell homeostasis as well as insure proper corneal epithelial differentiation. We propose
to test this hypothesis by focusing on how autophagy: (i) affects limbal epithelial stem cell proliferation; (ii)
regulates differentiation in the corneal epithelium; and (iii) is regulated by EphA2 in the corneal epithelium. To
accomplish these goals, we will capitalize on our ability to conduct gain- and loss-of-function studies of
autophagy-related genes and their key up-stream regulators in complimentary model systems that include
cultured human limbal (HLEKs) and corneal (HCEKs) epithelial cells, 3-D raft cultures of limbal and corneal
epithelia, and mouse models of impaired autophagy and EphA2 signaling. We will assess the functional
consequences of such modulations with a combination of morphogenetic (including Structured Illumination
Microscopy and TEM), biochemical, molecular biological, cell biological and physiological approaches. By
focusing on autophagy, our proposal represents a new approach to study the regulation of: (i) limbal stem and
TA cell proliferation; and (ii) corneal epithelial differentiation and nucelophagy. Such knowledge has clinical
applicability as sustaining proliferation is necessary for the proper expansion of cultured HLEKs used in ex vivo
transplantation as well as in wound healing. The impact of autophagy and nucleophagy on corneal epithelial
differentiation has translational relevance since aberrant differentiation is a feature of diseases of the corneal
epithelium (e.g., aniridia, chemical burns) and modulation of autophagy-associated genes are potential
treatment modalities, Understanding how autophagy is regulated in corneal epithelium is essential as this
tissue is routinely subjected to stress, which requires a proper autophagic response to maintain homeostasis.
项目总结/文摘
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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ROBERT M LAVKER其他文献
ROBERT M LAVKER的其他文献
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{{ truncateString('ROBERT M LAVKER', 18)}}的其他基金
Reversing the ocular impact of NM and SM through novel therapies
通过新疗法扭转 NM 和 SM 对眼部的影响
- 批准号:
10282412 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
Reversing the ocular impact of NM and SM through novel therapies
通过新疗法扭转 NM 和 SM 对眼部的影响
- 批准号:
10682631 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
Barrier Damage and The Immune CascadeNorthwestern University CounterACT Center of Excellence (NUCCX)
屏障损伤和免疫级联西北大学 CounterACT 卓越中心 (NUCCX)
- 批准号:
10282406 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
Reversing the ocular impact of NM and SM through novel therapies
通过新疗法扭转 NM 和 SM 对眼部的影响
- 批准号:
10490420 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
Barrier Damage and The Immune CascadeNorthwestern University CounterACT Center of Excellence (NUCCX)
屏障损伤和免疫级联西北大学 CounterACT 卓越中心 (NUCCX)
- 批准号:
10682598 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
Barrier Damage and The Immune CascadeNorthwestern University CounterACT Center of Excellence (NUCCX)
屏障损伤和免疫级联西北大学 CounterACT 卓越中心 (NUCCX)
- 批准号:
10490379 - 财政年份:2021
- 资助金额:
$ 48.08万 - 项目类别:
The Roles of Autophagy in Limbal/Corneal Epithelia.
自噬在角膜缘/角膜上皮中的作用。
- 批准号:
10225304 - 财政年份:2018
- 资助金额:
$ 48.08万 - 项目类别:
The Roles of Autophagy in Limbal/Corneal Epithelia.
自噬在角膜缘/角膜上皮中的作用。
- 批准号:
9910410 - 财政年份:2018
- 资助金额:
$ 48.08万 - 项目类别:
2016 Cornea, Biology and Pathobiology Gordon Research Conference & Gordon Research Seminar
2016年角膜、生物学和病理学戈登研究会议
- 批准号:
9052308 - 财政年份:2015
- 资助金额:
$ 48.08万 - 项目类别:
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