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 #
5R01EY011721-19
Application #
9242627
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
1997-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
19
Fiscal Year
2017
Total Cost
$708,298
Indirect Cost
$303,556
Name
Jackson Laboratory
Department
Type
Research Institutes
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Harder, Jeffrey M; Braine, Catherine E; Williams, Pete A et al. (2017) Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U S A 114:E3839-E3848
Williams, Pete A; Harder, Jeffrey M; Foxworth, Nicole E et al. (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756-760
Alavi, Marcel V; Mao, Mao; Pawlikowski, Bradley T et al. (2016) Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep 6:18602
Nair, K Saidas; Cosma, Mihai; Raghupathy, Narayanan et al. (2016) YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17. Dis Model Mech 9:863-71
Zhang, Ying; Fan, Jieqing; Ho, Joshua W K et al. (2016) Crim1 regulates integrin signaling in murine lens development. Development 143:356-66
Williams, Pete A; Tribble, James R; Pepper, Keating W et al. (2016) Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener 11:26
Kizhatil, Krishnakumar; Chlebowski, Arthur; Tolman, Nicholas G et al. (2016) An In Vitro Perfusion System to Enhance Outflow Studies in Mouse Eyes. Invest Ophthalmol Vis Sci 57:5207-5215
Souma, Tomokazu; Tompson, Stuart W; Thomson, Benjamin R et al. (2016) Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest 126:2575-87
Silverman, Sean M; Kim, Byung-Jin; Howell, Garreth R et al. (2016) C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury. Mol Neurodegener 11:24
Graham, Leah C; Harder, Jeffrey M; Soto, Ileana et al. (2016) Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease. Sci Rep 6:21568

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