INTERCELLULAR COMMUNICATION IN THE LENS

..Our results demonstrate a new, robust means of regulating hemichannels through a combination of extracellular monovalent and divalent cations, principally Na+, K+, and Ca2+...

..Collectively, these data provide insight into Cx26 structure-function and the underlying bases for the phenotypes associated with KID syndrome patients carrying the D50N mutation. ..

..This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. ..

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..In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes...

..Collectively, these data suggest a mechanism of action for BQ(+) that involves modulation loop gating rather than channel block as a result of binding in the NT domain...

..These results indicate that MAPK signaling specifically modulates coupling mediated by Cx50 and that gap junctional communication and signal transduction pathways may interact in osmotic regulation during postnatal fiber development...

..These results indicate that metal ions access the cysteine side chains through the open pore and that closure of the loop gate involves movement of the TM1/E1 region that results in local narrowing of the large aqueous connexin pore...

..Thus, we demonstrate that both forms of voltage dependence are intrinsic gating mechanisms in Cx46 hemichannels and that the action of external divalent cations is to selectively modulate loop gating...

..To determine which connexins functionally contribute to epithelial cell coupling and proliferation, junctional coupling from epithelial cells of wild-type and knockin mice was examined...

..These results suggest the two types of channels interact and gate cooperatively...

..The differential efficacy of block by 2-APB of gap junction channels formed by different connexins may provide a useful tool that could be exploited in gap junction research to selectively block certain gap junction channel subtypes...

..These results suggest that unique interactions between mutant and wild-type lens connexins might underlie the development of various cataract phenotypes in humans. ..

..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..

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..Advancing our knowledge of normal lens function is essential for the future development of potential anti-cataract and presbyopia therapies. ..

..The program will be overseen and coordinated by an Administration core (A). ..

..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..

..They also will broaden the general paradigm of how an integrated system of intercellular communication contributes to the regulation of development in many tissues. ..

..This will prepare the basis for discovering small molecule inhibitors of aggregation, an approach that has already yielded some results in a number of neurodegenerative protein deposition diseases. ..

..This proposal studies a potential coping mechanism to DNA damage that involves changes in how damaged cells communicate with one another to maintain their function and viability. ..

..The information gained from this work will have a major impact on the rational design of therapeutics that could prevent cataract formation. ..

..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..

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..The proposed research is significant because results will be useful in defining better drugs and other therapeutics that potentially ameliorate connexin-related diseases. ..

..To achieve these goals we will use powerful techniques that combine laser capture microdissection, proteomics and dynamic light scattering (DLS). ..

..The objectives will be pursued using structure-function approach and performing cytological, biochemical and molecular biological experiments as appropriate to verify the results. ..

..Antioxidants will also be tested to see if binding them to organelles helps the RPE sustain normal organelle motility despite ongoing photic stress associated with aging. ..

..Since mutation of one lens-specific RG component, TDRD7, causes human cataracts, these studies will also provide fundamental information about cataract formation. ..

..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..

..The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts. ..

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