Non Fiber Cell Functions for the Beaded Filament Proteins

Project: Research project

Project Details

Description

Abstract Beaded Filaments (BFs) are a structurally and biochemically filamentous cytoskeletal structure found in
lens fiber cells. In 40 years, neither the BF nor the two proteins required for assembly of the BF (BF Proteins
CP49 and filensin), have been demonstrated in cells other than differentiated lens fiber cells. In Preliminary
Data, we show that BF proteins are expressed in lens epithelium, but also in a subset of biopsied human
cancers. Moreover, BF protein expression in lens epithelium is not in a filamentous structure, but instead in a
large vermiform structure, which is only expressed after 5 weeks of age. As cells near the bow region where
differentiation is triggered, the structure disappears. These data: 1) are the first to report (to our knowledge) the
expression of BF proteins outside of the fiber cell, and outside of the lens 2) suggest that the lens epithelium
may assemble a novel organelle/inclusion, and 3) that developmental switches are still being flipped in the lens
epithelium at 5 weeks of age. Thus, these observations suggest a previously unknown function for the BF
Proteins, both in the lens, and in non-lens tissue, and in both normal and pathologic biology. We have no idea
what this function is, and invoke this R21 to begin the process of establishing this/these function(s). Our lab has worked on Beaded Filaments and Intermediate Filaments for the past 25 years. In doing
so we have accumulated a combination of BF/IF tools, resources, and experience in lens biology, which
uniquely situates us to make progress in revealing this non-canonical BF protein function. Because of the
availability of these tools (CP49 knockout, filensin knockout, and vimentin-knockout animals, a range of
antibodies to BF proteins, vimentin, and several other lens proteins, cDNA constructs, etc) and because of the
limited availability of rare human tumor material, we focus these initial efforts on lens. There are, of course, a vast number of questions that can be asked about a novel structure, but the
R21 limitations constrain the scope of inquiry. For that reason we are proposing questions at three levels, the
molecular, cellular and tissue levels, to cast the widest net possible. The questions asked are guided by our
knowledge of lens, intermediate filaments, beaded filaments, and the literature on cellular organelles and
inclusions. Just as our previous work started with a fiber cell-specific cytoskeletal structure (the BF) and grew into
a general attack on the structure of Intermediate Filaments, we hope that these studies will transcend from lens
epithelial-specific to the broader field of cell biology.
StatusFinished
Effective start/end date7/1/146/30/16

Funding

  • National Institutes of Health: $233,250.00
  • National Institutes of Health: $190,487.00

ASJC

  • Medicine(all)

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