Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium that affects nearly 4% of the population above 40 years of age and accounts for the majority of transplants performed each year in the US. Despite the health and socioeconomic impact of the disorder, knowledge of the underlying mechanism and genetic load is sparse, with the only available treatment being corneal transplant surgery. In this grant application, we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD; and b) begin developing in vitro and in vivo models for the underlying genetic causes of FCD. Our work consists of three specific aims that draw from the strengths of an interdisciplinary team. First, we will expand our patient collection and quantitatively document progression in families linked to known FCD loci (including two novel loci uncovered by our group in the past year). Second, we will take advantage of the knock-in mouse model developed recently in our laboratory to understand the cellular basis of familial loss of function mutations in TCF8 in late-onset FCD families. Finally, taking advantage of our unique cohort, which is enriched for large, multigenerational families, we will identify novel genes for FCD using a combination of traditional genetics tools and exon capture coupled to next generation re- sequencing. These three aims represent a balance of valuable clinical and genetic analyses coupled with functional experiments designed to dissect the molecular components essential to corneal endothelial biology and understand biochemical and cellular mechanisms underlying the disease pathology. Completion of these studies will significantly enhance our understanding of the genetic basis of this common disorder, offer important new insights into its pathomechanism, and provide critical measures for establishing disease presentation and progression rates, which will be necessary for patient management and the design of novel therapeutic paradigms.

Public Health Relevance

This grant proposal continues to expand our understanding of the clinical presentation of Fuchs corneal dystrophy, and its underlying genetic basis, which will lead to development of better therapeutic models and treatment for a common corneal dystrophy that affects 4% of the population over age 40.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY028538-01
Application #
9426401
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Mckie, George Ann
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205