Project Details
Description
Project Abstract/Summary
Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed
world. While recent studies support that mitochondrial (mt) defects in the retinal pigment epithelium (RPE)
contribute to the pathogenesis of AMD, the causes of the dysfunction remains to be elucidated. Of the genetic
polymorphisms linked to AMD, one of the most prevalent occurs in the gene encoding complement factor H
(CFH). CFH is a negative regulator of the alternative complement pathway and protects against inappropriate
complement activation that can cause chronic inflammation. The rs1061170 single-nucleotide polymorphism
(SNP) in CFH, substituting a histidine at position 402 (Y402H) in the protein, is found in ~50% of AMD patients.
How this single amino acid change contributes to AMD pathogenesis is unclear. Therefore, the goal of our
proposed studies is to determine why the presence of the high risk CFH variant increases the prevalence of
AMD disease. These studies build on our published work showing increased mtDNA damage in the RPE of AMD
donors with the CFH high-risk SNP and a significant decrease in RPE mt function in induced pluripotent stem
cell (iPSC)-RPE derived from donors harboring the high-risk allele. To accomplish our goal, we will use our
collection of primary RPE and iPSC-derived RPE cultured from individuals phenotyped for AMD disease severity
and genotyped for CFH risk. We will also use gene editing to create reciprocal isogenic iPSC-RPE lines from
parent iPSCs containing either the CFH low or high risk allele. These model systems will be used to investigate
how the presence of the CFH high risk allele alters RPE mt function and the response of RPE to metabolic and
oxidative stressors. Aim 1 will test the hypothesis that intracellular complement regulates multiple cellular
pathways that affect mt homeostasis and investigate how the presence of high risk 402H CFH variant protein
alters these processes. Aim 2 will use a global metabolome and proteome approach to test the hypothesis that
there are differences in metabolic and stress responsive pathways in RPE derived from donors with either the
high or low risk CFH genotype. Findings from these studies will provide a comprehensive picture of the role of
CFH in regulating RPE mt function by identifying cellular changes responsible for the loss in mt function and
differences in stress response observed in RPE harboring the CFH high risk allele. This mechanistic insight
could help explain the difference in AMD prevalence in CFH low versus high risk individuals. Knowledge about
these differences may lead to development of therapies targeting the primary defect in a genetically defined
population of AMD patients, which in turn, could lead to a “personalized medicine” approach for treatment of
AMD.
Status | Active |
---|---|
Effective start/end date | 4/1/18 → 6/30/24 |
Funding
- National Eye Institute: $452,969.00
- National Eye Institute: $434,899.00
- National Eye Institute: $452,234.00
- National Eye Institute: $132,609.00
- National Eye Institute: $452,969.00
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