Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells
了解角膜内皮细胞中的内质网-线粒体交互作用
基本信息
- 批准号:10550019
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAdenosine TriphosphateAffectAgeAntioxidantsApoptosisApoptoticAwardBioenergeticsBiological AvailabilityBiologyBlindnessCell DeathCell LineCellular biologyCollaborationsComplexCorneaCorneal EndotheliumDNA DamageDataDegenerative DisorderDepositionDevelopmentDiseaseDown-RegulationEconomicsEndoplasmic ReticulumEndothelial CellsEndotheliumExtracellular MatrixExtracellular Matrix ProteinsFemaleFuchs&apos Endothelial DystrophyGenetic TranscriptionGlareGoalsHumanIn VitroIncidenceInterventionInvestigationKeratoplastyLearningLinkMediatingMedicalMembrane PotentialsMentorsMitochondriaMitochondrial DNAMorphologyMusNQO1 geneOxidantsOxidative StressOxidoreductaseOxygen ConsumptionPathogenesisPathway interactionsPatientsPersonsPharmacological TreatmentPhasePopulationPredispositionProductionProteinsQuinonesReactive Oxygen SpeciesReportingResearch ActivityResearch PersonnelResource DevelopmentRoleSignal TransductionStressStructureTissuesTrainingUVA inducedUp-RegulationVisualage relatedantioxidant enzymebiological adaptation to stresscareer developmentdefined contributionendoplasmic reticulum stressin vitro Modelin vivoin vivo Modelinsightlight scatteringmedical schoolsmitochondrial dysfunctionmitochondrial membranemouse modelnoveloxidative DNA damageresponsesocial
项目摘要
Project Summary
Fuchs endothelial corneal dystrophy (FECD) is a common, genetically complex and age-related degenerative
disease affecting approximately 4 % of the U.S.A. population with a higher incidence in females. In FECD,
corneal endothelial (CE) cell loss is accompanied by extracellular matrix deposition in the form of guttae. My
mentor (Ula V. Jurkunas) has reported explicitly that in FECD, oxidant-antioxidant imbalance due to suboptimum
Nrf-2 regulated antioxidant defense, including a decline in its transcriptional target, NAD(P)H quinone
dehydrogenase 1 (NQO1), leads to oxidative DNA damage, mitochondrial dysfunction, and apoptosis. My
preliminary data also suggests the significant loss of CE in NQO1-/- mice compared to WT in the mouse model
of FECD. Alike oxidative stress and mitochondrial damage, my co-mentor (Albert S. Jun) and others have
implicated the role of ER stress/ Unfolded protein response (UPR) in the pathogenesis of FECD. My preliminary
data also suggests the significant and earlier activation of pro-apoptotic ER stress markers for NQO-/- cell line
after UVA-induced FECD model in vitro. However, there has not been any study linking ER and mitochondrial
stress under oxidant-antioxidant imbalance for CE in FECD. The objective of this proposal is to define the
contribution of ER stress on mitochondrial stress (altered bioenergetics and dynamics) under oxidant-antioxidant
imbalance in FECD. During the mentored phase (K99) of the award, I will determine whether UVA induces ER
and mitochondrial stress (Aim 1a), ER stress alters mitochondrial bioenergetic (Aim 1b) and dynamics
(morphology, fragmentation, translocation) all under oxidant-antioxidant imbalance (Aim 2a). I will learn to induce
and quantify ER stress with my co-mentor lab’s collaboration (Albert Jun), analyze mitochondrial bioenergetics
and dynamics with mentor Ula Jurkunas and co-mentor Pere Puigserver’s lab, learn in vitro and in vivo model of
FECD (Jurkunas’s lab) along with the extensive career development activities offered at Harvard Medical School.
During the R00 phase, with mentor and co-mentor’s support, I will perform uncompleted parts of Aim1-2 with the
additional investigation of the mechanism of ER mediated-activation of mitochondrial intrinsic apoptotic pathway
(Aim 1c) via Ca+2 signaling and microtubular rearrangement (Aim 2b). Collectively, these studies will provide new
insights and perspectives into the ER-Mitochondrial cross talk for corneal endothelial biology, which will advance
our understanding of FECD pathogenesis. A K99 award will allow me to receive additional training in ER and
Mitochondria biology along with novel training in corneal endothelial cell biology. The extensive resources and
career development opportunities available at Harvard Medical School, Jurkunas, Puigserver, and Jun’s lab, as
well as the research activities planned in the K99 phase, will enable me to achieve the long-term goal of
becoming an independent investigator dedicated to the study of ER-Mitochondrial cross talk in corneal
endothelial biology.
项目总结
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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Varun Kumar其他文献
Varun Kumar的其他文献
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{{ truncateString('Varun Kumar', 18)}}的其他基金
Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells
了解角膜内皮细胞中的内质网-线粒体交互作用
- 批准号:
10597212 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
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