Gap junctions formed by connexins are known to be essential for maintaining metabolic homeostasis of eye lens. We as well as others have recently revealed a novel feature of the lens connexin, which was found to be functionally involved in promoting epithelial-fiber differentiation and lens development. Our long-range goal is to understand the regulatory mechanisms and functional significance of gap junctions and their component, connexins in lens development and homeostasis. The objective of this application is to understand the mechanistic roles of Cx45.6 in cell differentiation, and in lens growth and development. The central hypothesis is that Cx45.6, unlike two other types of lens connexins, is functionally involved in the differentiation process and the formation of mature lens fibers. This hypothesis has been formulated on the basis of our significant preliminary findings, which demonstrate that Cx45.6 expression enhances lens epithelial-fiber differentiation and Cx45.6 is posttranslationally regulated by caspase-3 that is actively involved in terminal lens differentiation.
Three specific aims will be pursued: 1). Determine the functional involvement of Cx45.6 expression in epithelial-fiber differentiation and lens development; 2). Identify functional domain(s) of the Cx45.6 molecule important for the stimulatory effect on lens differentiation and characterize the interactions between Cx45.6 and MIP, and other potential factor(s), and 3). Determine the functional significance of caspase-3-mediated cleavage of Cx45.6. One of the innovative aspects is that this proposal aims to dissect the mechanisms of an unconventional function of lens connexin. Moreover, the research program will be accomplished using our established avian retroviral approaches as the principal tool for experimental manipulations of primary chick lens cultures as well as in vivo chick lenses. It is our expectation that our experimental findings will provide the molecular basis for understanding the functions and regulation of Cx45.6 in differentiating lens fibers and have a major impact on defining how gap junctions are involved in lens growth and development. The outcomes of our research will be significant because the new knowledge discovered will contribute to a broader understanding of gap junctions and connexins in cell differentiation and tissue development. Furthermore, this research activity should make a contribution to the therapeutic strategies for the treatment of eye diseases such as cataracts and provide new ideas for potential targets for drug discovery and development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012085-08
Application #
6844632
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1998-02-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
8
Fiscal Year
2005
Total Cost
$300,120
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Iyyathurai, Jegan; Wang, Nan; D'hondt, Catheleyne et al. (2018) The SH3-binding domain of Cx43 participates in loop/tail interactions critical for Cx43-hemichannel activity. Cell Mol Life Sci 75:2059-2073
Shi, Wen; Riquelme, Manuel A; Gu, Sumin et al. (2018) Connexin hemichannels mediate glutathione transport and protect lens fiber cells from oxidative stress. J Cell Sci 131:
Hu, Zhengping; Riquelme, Manuel A; Wang, Bin et al. (2018) Cataract-associated connexin 46 mutation alters its interaction with calmodulin and function of hemichannels. J Biol Chem 293:2573-2585
Tarzemany, Rana; Jiang, Guoqiao; Jiang, Jean X et al. (2018) Connexin 43 regulates the expression of wound healing-related genes in human gingival and skin fibroblasts. Exp Cell Res 367:150-161
Tarzemany, Rana; Jiang, Guoqiao; Jiang, Jean X et al. (2017) Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts. Sci Rep 7:14157
Xu, Huiyun; Liu, Ruofei; Ning, Dandan et al. (2017) Biological responses of osteocytic connexin 43 hemichannels to simulated microgravity. J Orthop Res 35:1195-1202
Hu, Zhengping; Shi, Wen; Riquelme, Manuel A et al. (2017) Connexin 50 Functions as an Adhesive Molecule and Promotes Lens Cell Differentiation. Sci Rep 7:5298
Roy, Sayon; Jiang, Jean X; Li, An-Fei et al. (2017) Connexin channel and its role in diabetic retinopathy. Prog Retin Eye Res 61:35-59
Zhou, J Z; Riquelme, M A; Gu, S et al. (2016) Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis. Oncogene 35:5597-5607
Shi, Qian; Jiang, Jean X (2016) Connexin arrests the cell cycle through cytosolic retention of an E3 ligase. Mol Cell Oncol 3:e1132119

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