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Project Details

Reactive ocular aldehyde in degenerative retinal diseases

Project Number5R01EY022658-03

Contact PI/Project LeaderMAEDA, AKIKO

Awardee OrganizationCASE WESTERN RESERVE UNIVERSITY

Description

Abstract Text

DESCRIPTION (provided by applicant): Prior studies implicate the role of the reactive retinal aldehyde, all-trans-retinal (atRAL) in degenerative retinal diseases such as Stargardt's disease and age-related macular degeneration and contributions of inflammatory responses to those diseases. Although continuous generation of atRAL by the visual (retinoid) cycle is required to maintain vision, chronic exposure to atRAL may serve as an endogenous stress inducer that can cause low-grade chronic inflammation. Two characteristic features of low-grade chronic inflammation in the retina are complement deposition at Bruch's membrane and invasive immune cells into the subretinal space. Our previous studies provided the following notable findings: (1) Rdh8-/-Abca4-/- mice with delayed atRAL clearance from the retina that develop cone-rod dystrophy also display complement deposition at Bruch's membrane. (2) Subretinal accumulation of microglia/macrophages in Rdh8-/-Abca4-/- mice. (3) Tlr3-/- Rdh8-/-Abca4-/- mice displayed milder retinal degeneration with less inflammatory changes compared to Rdh8-/- Abca4-/- mice. These observations strongly indicate that retinal inflammation is caused by the biological responses to atRAL, and this inflammation greatly contributes to age-related disorders of the retina. We propose three specific aims to examine the role of atRAL in retinal inflammation that may contribute to retinal tissue damages. In Aim 1, the role of atRAL for recruitment of immune cells to the subretinal space will be examined. Retinal microglial behavior will be investigated in Rdh8-/-Abca4-/- mice after light which causes accumulation of atRAL using in vivo scanning laser ophthalmoscopic and two-photon microscopic imaging and immunohistochemical analysis. Changes in chemokine/cytokine production in the retina of Rdh8-/-Abca4-/- mice will be examined with RNA analyses. Aim 2 will test the hypothesis that CCL3 is a major chemokine that mediates recruitment of inflammatory cells to the subretinal space in retinal degeneration caused by atRAL accumulation, because our preliminary study show ~80-fold increase of CCL3 production along with increased numbers of immune cells in the subretinal space of Rdh8-/-Abca4-/- mice. Effects of CCL3 will be investigated in degenerative phenotypes of Rdh8-/-Abca4-/- mice by creating Ccl3-/-Rdh8-/-Abca4-/- mice, and by subretinal CCL3 injection to WT mice. TLR3-medicated CCL3 production will also be examined using Tlr3-/-Rdh8-/-Abca4-/- mice that showed milder retinal degeneration with less inflammatory changes. In Aim 3, we will test the hypothesis that invasive immune cells contribute to retinal tissue damage by employing macrophage-depletion in mice with genetic and pharmacologic approaches and drug treatments with microglial inhibitors to Rdh8-/- Abca4-/- mice, and by in vitro experiments using co-culture of primary RPE and retinal microglial cells. Experimental results of these interrelated aims outlined in this application will determine the rol of atRAL in retinal inflammation and degeneration, and also will aid in the development of a new therapeutic concept whether atRAL is an appropriate therapeutic target for age-related retinal disorders.

Public Health Relevance Statement

The number of persons who are legally blind in the USA exceeds 1.3 million with 8-10 million aging persons who are afflicted with retinal degenerative diseases. Utilizing a mechanistically relevant model of Stargardt's macular degeneration with similar phenotypes observed in age-related macular degeneration, we have demonstrated that all-trans-retinal is one of the strongest candidate targets for the treatment of these grievous diseases. The goal of this proposed research is to characterize the detrimental effects of all-trans-retinal in retinal degeneration and to develop improved therapies by targeting this molecule.

NIH Spending Category

AgingEye Disease and Disorders of VisionMacular DegenerationNeurodegenerativeNeurosciences

Project Terms

ATP-Binding Cassette TransportersAcuteAgeAge related macular degenerationAgingAldehydesAminesAppearanceAtherosclerosisBehaviorBiologicalBruch's basal membrane structureCCL3 geneCell DeathCell SurvivalCellsCharacteristicsChronicCoculture TechniquesComplementComplement component C1DataDepositionDevelopmentDiabetes MellitusDiseaseEthanolaminesEventExhibitsExposure toFigs - dietaryGenerationsGeneticGoalsHomeostasisHumanImageImaging TechniquesImmuneImmune systemIn VitroInflammationInflammatoryInflammatory ResponseInjection of therapeutic agentKnowledgeLasersLeadLightLightingLinkLipofuscinMacular degenerationMaintenanceMediatingMicrogliaMicroscopicModelingMusMutationNerve DegenerationPathway interactionsPersonsPharmaceutical PreparationsPhenotypePhotoreceptorsPhysical condensationProductionRNAReportingResearchRetinaRetinalRetinal DegenerationRetinal DiseasesRetinitis PigmentosaRetinoidsRetinol dehydrogenaseRoleScanningSeveritiesSolidStargardt's diseaseStressStructure of retinal pigment epitheliumTLR3 geneTestingTissuesVisionVisualVitamin AWorkage relatedchemokinecytokinecytotoxicityhigh riskhuman TLR3 proteinimprovedin vivoin vivo imaginginhibitor/antagonistlegally blindmacrophagemouse modelnovel therapeuticsresearch studyresponseretinal damagesubretinal injectiontherapeutic targettwo-photon

Details

Contact PI/ Project Leader

Name

MAEDA, AKIKO

Title

Contact

Other PIs

Not Applicable

Program Official

Name

MCKIE, GEORGE ANN

Contact

Organization

Name

CASE WESTERN RESERVE UNIVERSITY

City

CLEVELAND

Country

UNITED STATES (US)

Department Type

OPHTHALMOLOGY

Organization Type

SCHOOLS OF MEDICINE

State Code

Congressional District

Other Information

Opportunity Number

PA-10-067

Study Section

Diseases and Pathophysiology of the Visual System Study Section[DPVS]

Fiscal Year

2014

Award Notice Date

01-July-2014

Administering Institutes or Centers

National Eye Institute

CFDA Code

867

DUNS Number

077758407

UEI

HJMKEF7EJW69

Project Start Date

01-August-2012

Project End Date

31-July-2017

Budget Start Date

01-August-2014

Budget End Date

31-July-2015

Project Funding Information for 2014

Total Funding

$384,650

Direct Costs

$245,000

Indirect Costs

$139,650

Year	Funding IC	FY Total Cost by IC
2014	National Eye Institute	$384,650

NIH Categorical SpendingClick here for more information on NIH Categorical Spending

Funding IC	FY Total Cost by IC	NIH Spending Category
NATIONAL EYE INSTITUTE	$384,650	Aging; Eye Disease and Disorders of Vision; Macular Degeneration; Neurodegenerative; Neurosciences

Sub Projects

No Sub Projects information available for 5R01EY022658-03

Publications

Publications are associated with projects, but cannot be identified with any particular year of the project or fiscal year of funding. This is due to the continuous and cumulative nature of knowledge generation across the life of a project and the sometimes long and variable publishing timeline. Similarly, for multi-component projects, publications are associated with the parent core project and not with individual sub-projects.

No Publications available for 5R01EY022658-03

Patents

No Patents information available for 5R01EY022658-03

Outcomes

The Project Outcomes shown here are displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed are those of the PI and do not necessarily reflect the views of the National Institutes of Health. NIH has not endorsed the content below.

No Outcomes available for 5R01EY022658-03

Clinical Studies

No Clinical Studies information available for 5R01EY022658-03

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