Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for slowing this form of AMD is to take high-dose vitamin and mineral supplements daily. Emerging evidence suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized by complement activation, production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. However, in general, there is a lack of knowledge regarding how these macular degenerations develop. Furthermore, there are no effective treatments for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new therapies for them. In this proposal we plan to i) test genetic strategies directed at preventing the secretion of misfolded R345W F3 from RPE cells, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of R345W F3 misfolding, and iii) test whether WT F3 is also necessary for sub-RPE deposit formation. At the end of the study, we hope to have a better understanding of the molecular basis by which misfolded F3-facilitates inflammation and sub-RPE protein deposition, and to identify a number of therapeutically- tractable approaches for treating ML. The insight that we gain regarding how misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to prevalent retinal diseases such as dry AMD.

Public Health Relevance

Age-related macular degeneration (AMD) is a complex and prevalent blinding disease that affects millions of Americans. Increasing evidence suggests that alterations in a protein, fibulin- 3, play a role in the initiation and propagation of key phenomena in AMD. This project will identify how these alterations in fibulin-3 ultimately trigger phenotypes in observed in AMD, thereby uncovering potential therapeutic strategies to treat AMD and similar, fibulin-3-based diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY027785-04
Application #
10086866
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Gordiyenko, Nataliya
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390