Show simple item record

dc.contributor.advisorBernstein, Audrey
dc.contributor.authorPhillips, Andrew
dc.date.accessioned2022-08-23T18:29:27Z
dc.date.available2022-08-23T18:29:27Z
dc.date.issued2022-08
dc.identifier.urihttp://hdl.handle.net/20.500.12648/7487
dc.description.abstractScarring in the cornea obstructs the refraction of incoming light onto the retina causing visual disability. Both acute scarring and chronic fibrosis are characterized by an accumulation of disorganized extracellular matrix (ECM). Disorganized ECM is deposited into the wound by specialized cells termed myofibroblasts. Pathological myofibroblasts are characterized by the expression of the highly contractile alpha smooth muscle actin (a-SMA) and the av-family of integrins (avb1,b3, b5, b6). The persistence of myofibroblasts in a healing wound promotes an autocrine loop of TGFb activity, over contraction of tissue, deposition of fibrotic ECM proteins, and ultimately the generation of scar tissue. My work is focused on the relative contribute of the deubiquitinase, USP10 to scarring in the cornea. I found that after wounding an increase in the expression of USP10 leads to deubiquitination of integrins and a subsequent increase in integrin recycling and matrix deposition. Knockdown of USP10 in vivo after corneal wounding significantly reduced the presence of myofibroblasts and immune cells in the healing wound, and corneal scarring. Through a yeast 2-hybrid screen I also identified a novel USP10 interacting protein, the formin Daam1. I found that Daam1 sequesters USP10 on actin stress fibers inhibiting its activity. Under pathological conditions, the expression of both USP10 and Daam1 are increased. My data suggest that Daam1 acts as a cellular reservoir, adding a layer of homeostatic control over USP10 activity and integrin function. Although defects in protein degradation have been identified as a major contributor to many diseases, together, my studies indicate that protein degradation (ubiquitin) pathways need to be considered in the context of integrin biology and in the pathogenesis of fibrotic healing.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectfibrosisen_US
dc.subjectfibronectinen_US
dc.subjectextracellular matrixen_US
dc.subjectscarringen_US
dc.subjectcorneaen_US
dc.titleRegulation of fibrosis through the ubiquitin pathwayen_US
dc.typeDissertationen_US
dc.description.versionNAen_US
refterms.dateFOA2022-08-23T18:29:28Z
dc.description.institutionUpstate Medical Universityen_US
dc.description.departmentBiochemistry & Molecular Biologyen_US
dc.description.degreelevelPhDen_US


Files in this item

Thumbnail
Name:
PhillipsDissertation2022.pdf
Size:
14.74Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International