Age-related macular degeneration (AMD) is a major cause of blindness that is characterized by pathologic changes at the retinal pigment epithelium-choriocapillaris interface. We recently found that vascular loss of the choriocapillaris is relatedto the earliest clinical signs of AMD, and that a reduced vascular density and increased number of """"""""ghost"""""""" vessels are related to the size and number of drusen and other subRPE deposits. Activation of the terminal complement pathway and formation of the membrane attack complex (MAC) at the level of the choriocapillaris is a likely cause of vascular loss in AMD. In this proposal we seek to identify the molecular and cellular responses of choroidal endothelial cells injured by MAC;to identify small molecules that protect choroidal endothelial cells against MAC-mediated lysis;and to develop and test avenues for the eventual replacement of lost endothelial cells. We anticipate that completion of these aims will result in important new understanding of mechanisms of protecting the choroid in early AMD, which may lead to new therapies for this blinding disease.

Public Health Relevance

Age-related macular degeneration is a devastating and common disease that can lead to blindness. We recently found that loss of blood vessels appears to play an important role in the earliest stages of macular degeneration. The goal of this research program is to pursue new treatments for AMD by determining how blood vessel cells respond to injury by the immune system, how to rescue existing blood vessel cells from damage, and to develop methods to replace damaged blood vessels using stem cells.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY024605-01
Application #
8752902
Study Section
(DPVS)
Program Officer
Shen, Grace L
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Sohn, Elliott H; Chirco, Kathleen R; Folk, James C et al. (2016) CLINICOPATHOLOGICAL CORRELATION IN A PATIENT WITH PREVIOUSLY TREATED BIRDSHOT CHORIORETINOPATHY. Retin Cases Brief Rep :
DeLuca, Adam P; Whitmore, S Scott; Barnes, Jenna et al. (2016) Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis. Hum Mol Genet 25:44-56
Zeng, Shemin; Whitmore, S Scott; Sohn, Elliott H et al. (2016) Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration. J Pathol 238:446-56
Giacalone, Joseph C; Wiley, Luke A; Burnight, Erin R et al. (2016) Concise Review: Patient-Specific Stem Cells to Interrogate Inherited Eye Disease. Stem Cells Transl Med 5:132-40
Wiley, Luke A; Beebe, David C; Mullins, Robert F et al. (2016) A Method for Sectioning and Immunohistochemical Analysis of Stem Cell-Derived 3-D Organoids. Curr Protoc Stem Cell Biol 37:1C.19.1-1C.19.11
Wiley, Luke A; Burnight, Erin R; DeLuca, Adam P et al. (2016) cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Sci Rep 6:30742
Worthington, Kristan S; Wiley, Luke A; Mullins, Robert F et al. (2016) Prevascularized silicon membranes for the enhancement of transport to implanted medical devices. J Biomed Mater Res B Appl Biomater 104:1602-1609
Small, Kent W; DeLuca, Adam P; Whitmore, S Scott et al. (2016) North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13. Ophthalmology 123:9-18
Chirco, Kathleen R; Tucker, Budd A; Stone, Edwin M et al. (2016) Selective accumulation of the complement membrane attack complex in aging choriocapillaris. Exp Eye Res 146:393-7
Whitmore, S Scott; Sohn, Elliott H; Chirco, Kathleen R et al. (2015) Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog Retin Eye Res 45:1-29

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