A recent study shows that mice deficient in the lens gap junction protein connexin 46 (Cx46) develop cataracts, indicating the direct role of gap junction-mediated communication in maintaining lens transparency. Gap junctions are clusters of transmembrane channels that connect the cytoplasm of adjacent cells. These channels permit small metabolites, ions and second messengers to pass from cell to cell. Lens fiber cells within the interior of the vertebrate eye lens have nether a blood supply nor organelles. Thus, lens survival and homeostasis are uniquely dependent on intercellular communication via gap junctions with epithelial cells at the lens surface. The chick lens is chosen as an experimental system as it provides many advantages compared with other species. Three connexins are known to participate in the formation of lens gap junction channels: Cx43 in lens epithelial cells, Cx45.6 and Cx56 mainly in lens fibers. Lens fiber proteins, which survive the whole life span of animals, are susceptible to post-translational phosphorylation. Phosphorylation of lens connexins may have functional implications in the regulation of lens gap junction channels. Moreover, evidence from other species has shown that phosphorylation of connexins is related to gap junction channel assembly and gating. The first goal of this proposal is to determine the functional role of connexin phosphorylation in the lens which includes: identifying phosphorylation sites, studying functional roles of connexin phosphorylation, and determining the relevant kinases involved. The second objective involves experiments to determine the signals for the correct targeting by different lens connexins and the formation of heteromeric connexins. The final objective involves the characterization of relationships between lens connexins and MIP and the function of MIP in lens gap junctions. The proposed experiments will be performed in established systems, including intact embryonic chicken lenses, primary lens cultures, connexin-deficient cell lines and Xenopus oocytes, In addition, a novel retroviral assay system, newly developed by the applicant, will be employed in which exogenous connexins will be introduced into the embryonic chick lens in situ in order to define the roles of lens gap junctions in lens physiology and pathology.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29EY012085-04
Application #
6350874
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Liberman, Ellen S
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
4
Fiscal Year
2001
Total Cost
$103,993
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
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:
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
Callaway, Danielle A; Riquelme, Manuel A; Sharma, Ramaswamy et al. (2015) Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress. Bone 76:40-8
Zhou, J Z; Riquelme, M A; Gao, X et al. (2015) Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncogene 34:1831-42
Shi, Qian; Gu, Sumin; Yu, X Sean et al. (2015) Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2. Dev Cell 35:483-96
Batra, Nidhi; Riquelme, Manuel A; Burra, Sirisha et al. (2014) Direct regulation of osteocytic connexin 43 hemichannels through AKT kinase activated by mechanical stimulation. J Biol Chem 289:10582-91
Biswas, Sondip K; Brako, Lawrence; Gu, Sumin et al. (2014) Regional changes of AQP0-dependent square array junction and gap junction associated with cortical cataract formation in the Emory mutant mouse. Exp Eye Res 127:132-42

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