Revised Abstract: The underlying pathology of cataract can often be demonstrated to involve defects in the differentiation of lens fiber cells from their proliferative transitional zone precursors. These studies seek to elucidate the mechanisms responsible for lens fiber cell differentiation by elucidating the mechanisms controlling the transcription of betaB1-crystallin, a gene expressed exclusively in differentiating lens fiber cells.
Specific aim one seeks to determine the molecular mechanisms that allow betaB1-crystallin to be expressed at nearly 3% of total cellular mRNA in the lens. This study is likely to give insight into how the single copy crystallin genes can contribute to the high concentrations of protein seen in the lens.
Specific aim two seeks to connect the observation that growth factor/receptor interactions control lens fiber cell differentiation to the transcriptional consequences of the signaling induced by these interactions. These investigations will allow us to connect growth factor signaling to the dramatic changes in gene expression coincident with the transition from an epithelial to a fiber cell.
Specific aim three seeks to determine the molecular mechanisms responsible for the redistribution of Prox1 protein during lens differentiation. These studies are critical to the understanding of how Prox1, a protein essential for fiber cell differentiation, functions in the lens. These complementary studies should provide insight into how lens fiber cell differentiation is controlled and how this process is disrupted during cataract formation.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VISA (01))
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Araj, Houmam H
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University of Delaware
Schools of Arts and Sciences
United States
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Audette, Dylan S; Scheiblin, David A; Duncan, Melinda K (2017) The molecular mechanisms underlying lens fiber elongation. Exp Eye Res 156:41-49
Audette, Dylan S; Anand, Deepti; So, Tammy et al. (2016) Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression. Development 143:318-28
Manthey, Abby L; Terrell, Anne M; Wang, Yan et al. (2014) The Zeb proteins ?EF1 and Sip1 may have distinct functions in lens cells following cataract surgery. Invest Ophthalmol Vis Sci 55:5445-55
Manthey, Abby L; Terrell, Anne M; Lachke, Salil A et al. (2014) Development of novel filtering criteria to analyze RNA-sequencing data obtained from the murine ocular lens during embryogenesis. Genom Data 2:369-374
Manthey, Abby L; Lachke, Salil A; FitzGerald, Paul G et al. (2014) Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. Mech Dev 131:86-110
Chatterjee, Sharmila; Wang, Yan; Duncan, Melinda K et al. (2013) Junctional adhesion molecule-A regulates vascular endothelial growth factor receptor-2 signaling-dependent mouse corneal wound healing. PLoS One 8:e63674
Grabitz, Abby L; Duncan, Melinda K (2012) Focus on molecules: Smad Interacting Protein 1 (Sip1, ZEB2, ZFHX1B). Exp Eye Res 101:105-6
Parthasarathy, Geetha; Ma, Bo; Zhang, Cheng et al. (2011) Expression of ?A3/A1-crystallin in the developing and adult rat eye. J Mol Histol 42:59-69
Duncan, Melinda K (2011) Development. A new focus on RNA in the lens. Science 331:1523-4
Chen, Xiaoren; Taube, Jennifer R; Simirskii, Vladimir I et al. (2008) Dual roles for Prox1 in the regulation of the chicken betaB1-crystallin promoter. Invest Ophthalmol Vis Sci 49:1542-52

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