Deciphering the mechanisms associated with high-risk AMD genotypes for ARMS2/HTRA1 andcomplement factor H

Ended Cooperative Agreement Awarded Last action

Award ID
U01EY034669
Recipient
Awarding agency
Obligated
$2,431,300

Award facts

Assistance listing
93.867 Vision Research
Completion date
Originally
Funding
  • $2,012,407.00 Federal
  • $418,893.00 Non-federal
Place of performance
California, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
This U01 grant application is submitted in response to RFA EY-21-002 "age-related macular degeneration (AMD) integrative biology initiative", with the goal of determining if patient-derived induced pluripotent stem cell (IPSC)-retinal pigment epithelium (RPE) can be used to discover the underlying pathophysiology of AMD. Studies from our laboratory as well as those of others strongly support the use of IPSC-RPE to understand how specific single-nucleotide polymorphisms (SNP) associated with high risk for advanced AMD influences multiple biological processes in the RPE. Our studies will focus on two snps with the highest odds ratio for developing advanced AMD- age-related maculopathy susceptibility 2/high temperature requirement A1 (ARMS2/HTRA1) and complement factor H (CFH). We will use the IPSC developed by the NEI and the new york stem cell foundation (NYSCF) and differentiate the parent cells and their reciprocal isogenic lines into RPE using the protocol established in the bharti laboratory. The parent/isogenic lines provide an excellent model system for deciphering the molecular factors that determine how the presence of snps in one or both genes affect the response to stress. We will test the hypothesis that the presence of homozygous risk alleles for either ARMS2/HTRA1 or CFH, independent and in combination, have a negative impact on the RPE stress response. Furthermore, each genetic risk profile will have a unique stress response. Our proposed studies will integrate classical reductionist investigations, coupled with discovery-driven analyses, to test specific hypotheses. Aim 1 will focus on differentiating and characterizing IPSC-RPE cell lines from 10 AMD patients and their isogenic lines. Aim 2 will test the hypothesis that the presence of AMD high-risk snps alter the cellular response to stress by performing large-scale quantification of proteins and metabolites, coupled with MT functional assays. Parent cells and their isogenic lines will be compared to determine the impact on metabolism and the stress response in IPSC-RPE (I) with the CFH high-risk SNP and (II) for high risk ARMS2/HTRA1, alone or in combination with high risk CFH. These studies will address how the presence of specific risk variants affect RPE exposed to a physiologically relevant stress, an important GAP in knowledge of AMD pathogenesis. Knowledge about the molecular details has the potential to 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.

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $373,670 $0
Amendment $382,058 $0
Amendment $0 $0
Amendment $0 $0
Amendment $418,893 $0
Amendment $418,893 $418,893
Original award $418,893 $0

Subawards

Subrecipient Amount Awarded
West Virginia University The Co‐investigator (Co‐I) in the U01 project will use targeted metabolomics approach with liquid chromatography–mass spectrometry (LC‐MS) to quantify… $34,987
The Research Foundation For The State University Of New York Sample preparations, treatment method development/validation, LC/MS analysis, and relative protein quantification will be performed in collaboration with… $61,886
The Research Foundation For The State University Of New York Sample preparations, treatment method development/validation, LC/MS analysis and relative protein quantification will be performed in collaboration with Dr. Jun… $62,454
West Virginia University The Du Lab at the West Virginia University will be tasked the following work: 1. The Du Lab will use targeted metabolomics approach with liquid… $56,743
West Virginia University Research Corporation The Du Lab will use targeted metabolomics approach with liquid chromatography–mass spectrometry (LC-MS) to quantify intracellular and extracellular… $59,517

Quick answers

Who received award U01EY034669?

U01EY034669 was awarded to Doheny Eye Institute by National Eye Institute (National Institutes of Health) on September 30, 2022.

How much is award U01EY034669 worth?

$2,431,300 has been obligated on U01EY034669: $2,012,407 in federal funding and $418,893 in non-federal funding.

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