The long term objective of this project is to investigate the regulation of FGF signaling in lacrimal gland development, which has important implications for understanding the etiology of the diseased lacrimal gland in human. The lacrimal gland develops through a branching morphogenesis process primarily driven by FGF signaling, which itself is regulated by glycosaminoglycan in the extracellular space. This application will focus on the role of glycosaminoglycan in lacrimal gland development and determine how the glycosaminoglycan fine structure regulates FGF signaling. Specifically, mouse genetic models will be developed to test the functions of glycosaminoglycan biosynthetic genes in lacrimal gland development, biochemical assays will be performed to examine the interaction between glycosaminoglycan and FGF molecules, and finally, explant culture systems will be utilized to determine the requirement of glycosaminoglycan in FGF signaling. By investigating the regulation of FGF signaling in murine lacrimal gland, this project will both contribute to medical research in treating human congenital eye diseases and advance our understanding of the mesenchymal-epithelial interaction paradigm.

Public Health Relevance

This project investigates the mechanism of FGF signaling in lacrimal gland development. It is expected to contribute to our understanding of this important pathway in human development and disease, and inform future development of clinical interventions to treat dry eye syndrome.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018868-04
Application #
8206828
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2009-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$292,723
Indirect Cost
$102,643
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Cai, Zhigang; Grobe, Kay; Zhang, Xin (2014) Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis. Dev Dyn 243:1310-6
Hertzler-Schaefer, Kristina; Mathew, Grinu; Somani, Ally-Khan et al. (2014) Pten loss induces autocrine FGF signaling to promote skin tumorigenesis. Cell Rep 6:818-26
Cai, Zhigang; Tao, Chenqi; Li, Hongge et al. (2013) Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma. Development 140:2711-23
Carbe, Christian; Garg, Ankur; Cai, Zhigang et al. (2013) An allelic series at the paired box gene 6 (Pax6) locus reveals the functional specificity of Pax genes. J Biol Chem 288:12130-41
Carbe, Christian; Hertzler-Schaefer, Kristina; Zhang, Xin (2012) The functional role of the Meis/Prep-binding elements in Pax6 locus during pancreas and eye development. Dev Biol 363:320-9
Cai, Zhigang; Simons, David L; Fu, Xin-Yuan et al. (2011) Loss of Shp2-mediated mitogen-activated protein kinase signaling in Muller glial cells results in retinal degeneration. Mol Cell Biol 31:2973-83
Qu, Xiuxia; Carbe, Christian; Tao, Chenqi et al. (2011) Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. J Biol Chem 286:14435-44
Pan, Yi; Carbe, Christian; Powers, Andrea et al. (2010) Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development. Development 137:1085-93
Cai, Zhigang; Feng, Gen-Sheng; Zhang, Xin (2010) Temporal requirement of the protein tyrosine phosphatase Shp2 in establishing the neuronal fate in early retinal development. J Neurosci 30:4110-9