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BLR&D Research Career Scientist Award

BLR&D Research Career Scientist Award
BLR
批准号:
10451508
负责人:
NICHOLAS C. BRECHA
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-01 至 2027-03-31
关键词:
AMPA ReceptorsAcetylcholineAddressAffectAgingAmacrine CellsAnimalsAwardAxonBiologyBlindnessBlurred visionCalciumCell DeathCell SurvivalCell physiologyCellsChronicClinicalCommunicationCommunitiesCytoprotectionDRADA2b proteinDendritesDevelopmentDiabetic RetinopathyDiagnosisDiseaseEnzymesEyeEye InjuriesEye diseasesFeedbackFunctional disorderFundingGeneticGlaucomaGoalsHealthHealthcareInjuryInterneuronsInvestigationKnowledgeLong-Term EffectsMacular degenerationMammalsMediatingModelingNatureNeuronsOptic NerveOptic Nerve InjuriesPaperPathologicPeer ReviewPeptidesPermeabilityPharmacologyPharmacology StudyPhotophobiaPlayPopulationProsthesisPublishingQuality of lifeRecoveryRegulationReportingResearchRetinaRetinal DegenerationRetinal DiseasesRetinal Ganglion CellsRoleScienceScientistSeriesSignal TransductionSignaling MoleculeSmall Interfering RNASpermineStem cell transplantSynapsesSystemTestingTranscriptional RegulationTranslational RegulationTraumaTraumatic Brain InjuryUnited States Department of Veterans AffairsUnited States National Institutes of HealthVeteransVisionVision researchVisualVisual impairmentVisual system structureaging populationantagonistbasebiophysical propertiesblast exposurecareercell typechannel blockersdisabilityeffective therapyefficacious treatmentexperimental studyextracellulargabapentingamma-Aminobutyric Acidganglion cellgene therapyhorizontal cellimage processinginformation processingmild traumatic brain injurymilitary veterannerve injurynovel therapeutic interventionoptic nerve disorderpatient populationpreventprogramsresponseservice memberstem cell therapytreatment strategyuptakevisual dysfunctionvisual information

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中文摘要
翻译
这个视觉研究项目的长期目标是更好地理解这种机制
英文摘要
The long-term goal of this vision research program is to gain a better understanding of 1) the mechanisms underlying retinal synaptic and cellular physiology mediating visual image processing, and 2) the early cellular changes that are likely to mediate ganglion cell death and loss of vision following retinal and optic nerve disease and trauma. This program consists of two related components. 1) National Institute of Health supported studies are concerned with the functional organization of the mammalian retina by investigating synaptic and cellular mechanisms, and the role of retinal microcircuits in mediating image processing. This fundamental experimental component is focused on two classes of retinal interneurons, called amacrine and horizontal cells, their network connectivity, and the action of their signaling molecules that play a role in defined retinal circuits. These studies aim to advance our knowledge of normal cellular mechanisms mediating visual information processing in the retina. This information is key to understanding the pathophysiology of eye diseases, a required step for developing rational genetic and stem cell therapeutic approaches for preventing or treating retinal diseases such as glaucoma, macular degeneration, and diabetic retinopathy, which affect the Veteran population. 2) VA supported studies are concerned with understanding early mechanisms underlying retinal ganglion cell death due to retina and optic nerve disease and injury. Ocular trauma, which frequently occurs with traumatic brain injury (TBI), results in severe visual impairments, including acuity loss, photophobia, and partial and total loss of vision. The current Merit Review is focused on Ca2+ channel and calcium permeable AMPA receptor (CP-AMPAR) transcriptional and translational regulation and ganglion cell intracellular Ca2+ following optic nerve injury, as a model for optic nerve trauma. The first group of studies is focused on L- type Ca2+ channels expressed by ganglion cells, to elucidate the actions of the L-type Ca2+ channel blocker, lomerizine, which enhances ganglion cell survival in different models of optic neuropathy. Studies are evaluating L-type Ca2+ channel expression and function following optic nerve injury, and to test the idea that lomerizine blocks up-regulated Ca2+ channel function, which in turn slows intracellular retinal ganglion cell Ca2+ influx. This in turn would limit pathological changes including ganglion cell loss. Animal studies testing lomerizine administration on retinal ganglion cell survival are also planned. Related experimental studies are focused on testing if CP-AMPARs, which are reported to be rapidly up-regulated on retinal ganglion cell dendrites after ocular injury, mediate Ca2+ uptake into ganglion cells and contribute to ganglion cell death. Experiments are focused on defining CP-AMPAR and the AMPAR editing enzyme expression, and testing the idea that pharmacological antagonism, genetic and siRNA-mediated regulation of CP-AMPARs and the AMPA editing enzyme ADAR2 stabilize ganglion cell intracellular Ca2+ levels, and enhances ganglion cell survival following nerve injury. Animal studies will also test if selective CP-AMPAR antagonists and targeted siRNAs protect against retinal ganglion cell loss after optic nerve injury. The long-term goal of the Merit Review studies is to understand how vision loss associated with retinal ganglion cell death can be reduced. These studies have the potential impact of unveiling novel therapeutic approaches to ameliorate ocular damage and vision loss. These investigations are consistent with the health-related goals of the Department of Veteran Affairs to develop effective treatments for eye injuries.
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会议论文
VRC: Reduction of Vision Loss with Early Interventions After Optic Nerve Injury
BLR&D Research Career Scientist Award
Horizontal cell signaling in the mammalian retina
Horizontal cell signaling in the mammalian retina
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