Many human birth defects, diseases, and cancers arise when epithelial cells either acquire or lose specific behavioral characteristics. The long-term aims of this proposal are to understand the pathways that determine epithelial cell behavior in general and will focus specifically on the role Shrm-family proteins play in this process. These proteins are conserved in vertebrates and exhibit the modular nature suggestive of multi-functional adapters. Of the five predicted family members, only Shrm and Apx have been characterized to any extent. Both are expressed in epithelial cells and localize to apical membrane domains in vivo. In addition, the function of both Apx and Shrm appears linked to the actin cytoskeleton, as Shrm directly binds F-actin and Apx function seems to be regulated by the cytoskeleton. Finally, mouse embryonic development requires the Shrm protein, as Shrm-deficient embryos exhibit severe neural tube defects that resemble many seen in human conditions such as spina bifida, anencephaly, and facial clefting. Alteration in cytoskeletal organization or polarity appears to be the underlying defect. These data support the hypothesis that these proteins utilize their modular nature to regulate architectural characteristics of epithelial cells. Therefore the goal of the research proposed here is to elucidate the functions of Shrm/Apx proteins and determine what set of epithelial behaviors require these activities.
The specific aims are 1) Identify the nature and ramifications of Shrm protein-protein interactions and 2) Characterize the role of Shrm in epithelial cell biological pathways. Accomplishing these goals will require rigorous biochemical and cell biological analysis of Shrm and Shrm related proteins. Data obtained from this line of questioning will compliment a thorough analysis of the epithelial character of Shrm-null neuroepithelialcells. Together, these avenues of research should shed new light on pathways that control epithelial biology during the course of normal and adult life.
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