The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I will specifically investigate the roles of Arf, an important mammalian tumor suppressor gene, and Platelet-derived growth factor receptor 2 (Pdgfr2), which contributes to a variety of developmental, physiological, and pathological processes. To assure normal development, mammalian cells have mechanisms to check cell proliferation stimuli and preserve cell cycle arrest. When gone awry, excess mitogenic signals lead to developmental defects and a wide variety of pathological processes. The Arf gene product, p19Arf, was initially discovered to play a key role as a "fuse" to control excess mitogens and prevent tumor formation. Work supported by the first cycle of this R01 has challenged this simple paradigm as I have shown p19Arf plays an essential function during mouse eye development. Without it, excess numbers of perivascular cells envelop the hyaloid vasculature in the vitreous, preventing their normal involution during the later stages of eye development. Mice lacking Arf are blind due to a pathological process strikingly similar to severe persistent hyperplastic primary vitreous (PHPV). We have identified a new biochemical and genetic pathway in which the Arf gene product blocks signals stemming from Pdgfr2 to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. In the current proposal, I will tackle the critical questions that still cloud our understanding of the functional relationship between the two gene products. I will take advantage of existing cell culture system and mouse models one of which will be developed in this proposal to (1) identify how p19Arf- dependent control of Pdgfr2 influences eye development;(2) uncover mechanisms by with Pdgfr2 fosters vitreous hyperplasia without Arf;and (3) elucidate mechanisms by which Arf represses Pdgfr2 expression. Insight into how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals will address fundamental aspects of eye development;leave me ideally positioned to address whether genetic abnormalities in this new "pathway" contribute to the pathogenesis of PHPV or other vitreoretinopathies;and begin to investigate whether pharmacological disruption of Pdgfr2 signaling can ameliorate the disease.

Public Health Relevance

The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I have identified a new biochemical and genetic pathway in which the Arf gene product, p19Arf, blocks signals stemming from Platelet-derived growth factor receptor 2 (Pdgfr2) to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. I will use cell culture-based and mouse models to uncover how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014368-12
Application #
8336897
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2002-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2012
Total Cost
$381,586
Indirect Cost
$141,586
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Iqbal, Nida S; Xu, Lin; Devitt, Caitlin C et al. (2014) Isolation and characterization of mammalian cells expressing the Arf promoter during eye development. Biotechniques 56:239-49
Iqbal, Nida; Mei, Jie; Liu, Jing et al. (2014) miR-34a is essential for p19(Arf)-driven cell cycle arrest. Cell Cycle 13:792-800
Mary-Sinclair, Michelle N; Wang, Xiaofei; Swanson, Douglas J et al. (2014) Varied manifestations of persistent hyperplastic primary vitreous with graded somatic mosaic deletion of a single gene. Mol Vis 20:215-30
Zheng, Yanbin; Devitt, Caitlin; Liu, Jing et al. (2013) Arf induction by Tgf* is influenced by Sp1 and C/ebp* in opposing directions. PLoS One 8:e70371
Zheng, Yanbin; Devitt, Caitlin; Liu, Jing et al. (2013) A distant, cis-acting enhancer drives induction of Arf by Tgf* in the developing eye. Dev Biol 380:49-57
Freeman-Anderson, Natalie E; Zheng, Yanbin; McCalla-Martin, Amy C et al. (2009) Expression of the Arf tumor suppressor gene is controlled by Tgfbeta2 during development. Development 136:2081-9
Godinho, Leanne; Williams, Philip R; Claassen, Yvonne et al. (2007) Nonapical symmetric divisions underlie horizontal cell layer formation in the developing retina in vivo. Neuron 56:597-603
Thornton, J Derek; Swanson, Doug J; Mary, Michelle N et al. (2007) Persistent hyperplastic primary vitreous due to somatic mosaic deletion of the arf tumor suppressor. Invest Ophthalmol Vis Sci 48:491-9
Saab, Raya; Bills, Jennifer L; Miceli, Alexander P et al. (2006) Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. Mol Cancer Ther 5:1299-308
Silva, Ricardo L A; Thornton, J Derek; Martin, Amy C et al. (2005) Arf-dependent regulation of Pdgf signaling in perivascular cells in the developing mouse eye. EMBO J 24:2803-14

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