Connexins are the subunit proteins of gap junctions, which allow the exchange of ions, second messengers and small metabolites between adjacent cells through intercellular channels. Gap junctional communication is important in the development and maintenance of lens, as mutations in lens connexin genes cause cataract and developmental defects in humans and mice. Signal transduction pathways have also been shown to play critical roles in lens development and homeostasis, and mutations in signaling genes like phosphatase and tensin homolog (PTEN) cause complex human syndromic disorders that include cataract. Although great progress has been made, there are still substantial gaps in our knowledge about potential cooperation between these two different intercellular communication systems. In this proposal, our objective is to further define how gap junctional communication interacts with other intercellular signal transduction pathways in the lens. We propose first to examine the consequences of PI3K deficiency by generating and characterizing conditional knockout mice lacking the p110a and p110b catalytic subunits of PI3K in the lens. Second, we will make conditional knockout mice lacking PTEN in the lens, and examine their phenotype. Finally, we will investigate interactions between lens gap junctional coupling and the PI3K/Akt and PTEN signaling pathways in postnatal growth and homeostasis by using pharmacological blockers, electrophysiological measurements and biochemical assays in vitro. We will also cross PI3K and PTEN conditional knockout animals with connexin knockout mice to confirm interactions in vivo. These studies will provide insights into how gap junctional coupling and signal transduction pathways synergistically interact to regulate lens growth and homeostasis by combining in vitro pharmacological and electrophysiological assays with in vivo animal models. They also will broaden the general paradigm of how an integrated system of intercellular communication contributes to the regulation of development in many tissues.

Public Health Relevance

Mutations in connexin genes cause a broad spectrum of human health problems including cataract and ocular developmental defects in humans and mice. Mutations in phosphatase and tensin homolog (PTEN) cause a complex human syndromic disorder that includes cataract. Genetic studies have revealed much about cataract causing mutations in these different genes, but there are still substantial gaps in our knowledge about potential cooperation between these two different intercellular communication systems in preventing cataract in the normal lens. The proposed studies will further characterize these genes that cause congenital cataract, and also further characterize the control of the cell cycle in lens epithelia by integrated communication pathways.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013163-11
Application #
8248856
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (02))
Program Officer
Araj, Houmam H
Project Start
2000-07-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
11
Fiscal Year
2012
Total Cost
$422,184
Indirect Cost
$153,277
Name
State University New York Stony Brook
Department
Physiology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Rubinos, Clio; Villone, Krista; Mhaske, Pallavi V et al. (2014) Functional effects of Cx50 mutations associated with congenital cataracts. Am J Physiol Cell Physiol 306:C212-20
White, Thomas W (2013) Is half of a lens gap junction channel better than none? Focus on "properties of two cataract-associated mutations located in the NH2 terminus of connexin 46". Am J Physiol Cell Physiol 304:C821-2
Gao, Junyuan; Wang, Huan; Sun, Xiurong et al. (2013) The effects of age on lens transport. Invest Ophthalmol Vis Sci 54:7174-87
Gao, Junyuan; Sun, Xiurong; Moore, Leon C et al. (2013) The effect of size and species on lens intracellular hydrostatic pressure. Invest Ophthalmol Vis Sci 54:183-92
Ebihara, Lisa; Tong, Jun-Jie; Vertel, Barbara et al. (2011) Properties of connexin 46 hemichannels in dissociated lens fiber cells. Invest Ophthalmol Vis Sci 52:882-9
Gao, Junyuan; Sun, Xiurong; Moore, Leon C et al. (2011) Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling. J Gen Physiol 137:507-20
Tao, Liang; DeRosa, Adam M; White, Thomas W et al. (2010) Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin. Dev Dyn 239:2627-36
Mathias, Richard T; White, Thomas W; Gong, Xiaohua (2010) Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev 90:179-206
Li, Lin; Cheng, Catherine; Xia, Chun-hong et al. (2010) Connexin mediated cataract prevention in mice. PLoS One 5:
Lee, Jack R; White, Thomas W (2009) Connexin-26 mutations in deafness and skin disease. Expert Rev Mol Med 11:e35

Showing the most recent 10 out of 42 publications