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):

Report Date:

2015-12-01

Pagination or Media Count:

10.0

Abstract:

Fibrosis in scleroderma is associated with altered WntBeta-catenin signaling. This project seeks to define how Wnts activate fibrotic responses, to determine whether blocking WntBeta -catenin signaling can prevent or attenuate fibrosis in scleroderma, and to ascertain whether markers of WntBeta-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.

Subject Categories:

Distribution Statement:

APPROVED FOR PUBLIC RELEASE