Our goal is to identify and characterize new genes, pathways and molecular mechanisms that contribute to elevated IOP and glaucoma. This is a critical step for rationally improving the care of patients. Elevated intraocular pressure (IOP) isa major risk factor for glaucoma. The mechanisms underlying IOP elevation and glaucoma are largely unidentified. We study the genetics of glaucoma using both the human and mouse. Using mice to discover glaucoma pathways is an important approach, as mice are experimentally tractable, and it remains difficult to identify many glaucoma genes in patient populations.
(Aim 1) We will use the power of mouse genetics to identify novel genes and mechanisms that induce IOP elevation in new glaucoma-relevant mutants that we have discovered and started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the molecular pathogenesis. We will collaborate to assess the human orthologs of the identified genes in human patients.
(Aim 2) The limited availability of useful mutants remains a major factor hindering glaucoma gene discovery using mice. Thus, we will conduct a phenotype driven mutagenesis screen to identify novel genes and molecular mechanisms involved in IOP elevation and glaucoma. We propose a sensitized ENU screen for glaucoma mutations. We will sensitize the screen in various ways including a mutation in the mouse ortholog of a human gene that predisposes people to high IOP and glaucoma, a predisposition that we have repeated in mice. To hasten the discovery of glaucoma-relevant genes and mechanisms, we will complement genetics with state-of-the-art sequencing and genomic approaches. Continuing to use the power of a phenotype-driven mutagenesis screen, in parallel with our proven experience in determining disease mechanisms and in examining ocular phenotypes, will enable us to identify and characterize new genes and molecular processes that contribute to elevated IOP and glaucoma. The new mutants will have great potential to transform our understanding of glaucoma.

Public Health Relevance

Glaucoma is one of the leading causes of blindness. Over 20 regions of the human genome have been implicated in glaucoma, but very few genes have been identified. Our proposal aims to produce mouse models of human glaucoma to be used as tools to understand the mechanisms of glaucoma, to help identify human glaucoma genes and to test new treatments. We will also identify new glaucoma genes and mechanisms with the aim of providing information to improve patient care.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY011721-16A1
Application #
8695671
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
1997-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$787,000
Indirect Cost
$337,286
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Howell, Gareth R; MacNicoll, Katharine H; Braine, Catherine E et al. (2014) Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis 71:44-52
Howell, Gareth R; Soto, Ileana; Libby, Richard T et al. (2013) Intrinsic axonal degeneration pathways are critical for glaucomatous damage. Exp Neurol 246:54-61
Veth, Kerry N; Willer, Jason R; Collery, Ross F et al. (2011) Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma. PLoS Genet 7:e1001310
Lachke, Salil A; Alkuraya, Fowzan S; Kneeland, Stephen C et al. (2011) Mutations in the RNA granule component TDRD7 cause cataract and glaucoma. Science 331:1571-6