Accession Number : AD1014040


Title :   Aberrant Recapitulation of Developmental Program: Novel Target in Scleroderma


Descriptive Note : Technical Report,30 Sep 2012,29 Sep 2015


Corporate Author : Boston University Medical Campus Boston United States


Personal Author(s) : Lafyatis,Robert


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1014040.pdf


Report Date : 01 Dec 2015


Pagination or Media Count : 10


Abstract : Fibrosis in scleroderma is associated with altered Wnt/Beta-catenin signaling. This project seeks to define how Wnts activate fibrotic responses, to determine whether blocking Wnt/Beta -catenin signaling can prevent or attenuate fibrosis in scleroderma, and to ascertain whether markers of Wnt/Beta-catenin signaling can be used as biomarkers of disease activity, progression and severity, as well as tools to identify patient subsets that will respond to catenin-targeted therapy in a personalized or precision medicine strategy. We have previously shown that in scleroderma, fibrosis is consistently accompanied by subdermal fat loss and is associated with the down-regulation of PPAR-(peroxisome proliferator activated receptor), a master regulator of adipogenesis that signals through the adipokine adiponectin (APN). Circulating and tissue levels of adiponectin are significantly reduced in scleroderma. Here were port that APN causes a time-dependent down-regulation of both Wnt3a-induced canonical signaling and fibrotic responses at the mRNA and protein levels. Mechanistically, these effects involve suppression of both the expression and activation of the Wnt co-receptor low density lipoprotein receptor-related protein-6 (LRP6). These results demonstrate that adiponectin inhibits short-term-catenin signaling as well as the Wnt3a-mediated fibrotic response, identifying adiponectin as a natural anti-fibrotic agent with tremendous therapeutic potential.


Descriptors :   FIBROSIS , AUTOIMMUNE DISEASES , receptor sites (physiology) , therapy , electrophysiology , gene expression , fibroblasts , skin (anatomy) , lipoproteins , response (biology) , RHEUMATIC DISEASES


Distribution Statement : APPROVED FOR PUBLIC RELEASE