Connexin-forming gap junction intercellular communication (GJIC) is essential for the metabolic homeostasis of the lens. In addition to gap junctions, connexins forms hemichannels, permitting exchange of molecules across the cell. However, little is known regarding the function and regulation of hemichannels in the lens. In addition, lens connexin is subjected to posttranslational modifications;phosphorylation in differentiating lens fibers and proteolytic truncation in mature lens fibers. Our long-range goal i to understand the molecular mechanism(s) and functional significance of connexin molecules in lens homeostasis and transparency. The objective is to elucidate the distinctive, mechanistic roles of gap junctions and hemichannels, and role of posttranslational modifications of connexin (Cx) 50 under normal and oxidative stress conditions. The central hypotheses are: (1) GJIC and hemichannels play distinctive roles in the lens;(2) Increased GJIC and/or hemichannel function due to Cx50 phosphorylation by PKA in differentiating fibers and adaptive-regulation of gap junctions/hemichannels due to Cx50 truncation in mature fibers enhance lens resistance to oxidative damages.
Three specific aims will be pursued: 1) Determine the distinctive roles of gap junctions and hemichannels in the differentiating lens fibers. 2) Determine the functional importance of PKA phosphorylation of Cx50 in the lens. 3) Determine the mechanistic role of developmentally associated truncation of Cx50 in mature lens fibers. One of the innovative aspects is that this proposal aims to dissect distinctive roles of gap junctions and hemichannels, and posttranslational modifications in differentiating and mature lens fibers. Moreover, we will use our newly developed ex vivo approach to dissect the roles of Cx50 and its truncation in cortex and center core of the lens. It is our expectation that elucidation of the molecular mechanism(s) involved in the regulation of lens connexins and the channels formed by them will provide a better understanding of the general homeostatic process of lens under normal and pathological conditions. The outcomes of our research will be significant because the newly discovered knowledge should make novel and beneficial contributions to new strategies for the treatment of lens disorders, e.g. age-related cataracts, and pave way for drug discovery and development.

Public Health Relevance

Cataracts are one of the most common eye diseases and also one of the leading causes for blindness worldwide. Connexins play important roles in lens homeostasis and mutations in connexin genes lead to human congenital cataracts. The proposed research activity will help in understanding the molecular mechanism underlying the function of connexins under physiological and pathological conditions, and should make novel contributions to new ideas and strategies for drug discovery and development in treatment of cataracts.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012085-17
Application #
8708863
Study Section
(BVS)
Program Officer
Araj, Houmam H
Project Start
1998-02-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
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

Showing the most recent 10 out of 42 publications