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
Chirco, Kathleen R; Flamme-Wiese, Miles J; Wiley, Jill S et al. (2018) Evaluation of serum and ocular levels of membrane attack complex and C-reactive protein in CFH-genotyped human donors. Eye (Lond) 32:1740-1742
Chirco, Kathleen R; Lewis, Carly J; Scheetz, Todd E et al. (2018) Evaluation of sFLT1 protein levels in human eyes with the FLT1 rs9943922 polymorphism. Ophthalmic Genet 39:68-72
Zeng, Shemin; Wen, Kuo-Kuang; Workalemahu, Grefachew et al. (2018) Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury. Sci Rep 8:13387
Do, Anh-Vu; Worthington, Kristan S; Tucker, Budd A et al. (2018) Controlled drug delivery from 3D printed two-photon polymerized poly(ethylene glycol) dimethacrylate devices. Int J Pharm 552:217-224
Chirco, K R; Sohn, E H; Stone, E M et al. (2017) Structural and molecular changes in the aging choroid: implications for age-related macular degeneration. Eye (Lond) 31:10-25
Zhao, Zhenyang; Liang, Yuejin; Liu, Yin et al. (2017) Choroidal ?? T cells in protection against retinal pigment epithelium and retinal injury. FASEB J 31:4903-4916
Chirco, Kathleen R; Worthington, Kristan S; Flamme-Wiese, Miles J et al. (2017) Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies. Acta Biomater 57:293-303
Mullins, Robert F; Warwick, Alasdair N; Sohn, Elliott H et al. (2017) From compliment to insult: genetics of the complement system in physiology and disease in the human retina. Hum Mol Genet 26:R51-R57
Songstad, Allison E; Worthington, Kristan S; Chirco, Kathleen R et al. (2017) Connective Tissue Growth Factor Promotes Efficient Generation of Human Induced Pluripotent Stem Cell-Derived Choroidal Endothelium. Stem Cells Transl Med 6:1533-1546
Worthington, Kristan S; Wiley, Luke A; Kaalberg, Emily E et al. (2017) Two-photon polymerization for production of human iPSC-derived retinal cell grafts. Acta Biomater 55:385-395

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