Fibrosis is a pathologic process characterized by fibroblast proliferation (fibroproliferation) and abnormal accumulation of extracellular matrix (ECM). There are currently no effective targeted therapies to ameliorate this progressive process, and therefore fibrotic diseases lead to great morbidity and mortality as normal tissue architecture and organ function is lost. Fibrotic and fibroproliferative diseases, which contributeto 45% of deaths in the developed world, can involve connective tissues, as in scleroderma and keloid scar formation, and visceral organs, as in chronic obstructive pulmonary disease and diabetic nephropathy. The health care burden and individual hardship that result from fibrotic and fibroproliferative diseases call for disease-informed mechanistic investigations of fibrosis that will lead to the development of new, effective targeted therapies. Such therapies require improved understanding of the molecular abnormalities in fibroblasts, which are the key cellular mediators of fibrosis. Recent work has shown that activity of the canonical Wnt signaling pathway and its primary transducer, -catenin, is elevated in fibrotic skin, kidney, and lung disease and animal models. Increased activity of -catenin has since been demonstrated to be sufficient in dermal fibroblasts for spontaneous and progressive skin fibrosis in an in vivo mouse model. There is a growing body of evidence that supports -catenin, which has known roles regulating target gene expression during development and disease, as a central mediator in fibrotic processes and a potential therapeutic target. However, it is not known whether -catenin is required during the progression of fibrosis, nor is its pro-fibrotic mechanism understood. This proposal will test the hypothesis that increased -catenin activity in fibroblasts results in characteristic gene expression changes to promote matrix accumulation and fibroproliferation in fibrosis.
Aim 1 will test the requirement for -catenin in fibrosis of mature skin by inducing expression of constitutively active -catenin in mouse dermal fibroblasts in vivo to generate a fibrotic phenotype, then removing expression of activated -catenin and evaluating whether skin fibrosis is attenuated.
Aim 2 will identify a pro-fibrotic -catenin- dependent gene expression signature by examining differential gene expression in dermal fibroblasts of activated -catenin mutant mice. This signature will then be integrated with the changes in gene expression that occur in a panel of human fibrotic skin diseases in order to define a -catenin activation signature in pathologic fibrosis. The results of these proposed experiments will define the required role for nuclear -catenin activity in fibrogenesis in vivo and will establish -catenin a a potential target for novel anti-fibrotic therapies.

Public Health Relevance

Fibrosis is an irreversible pathologic process that leads to loss of normal tissue structure and organ function in numerous diseases. This project will investigate how changes in the regulation of gene expression contribute to fibrosis of skin in scleroderma; keloid scar formation; and other diseases. Understanding the molecular mechanisms that contribute to fibrosis is essential for the design of effective therapy for fibrotic diseases in skin and other organs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30AG045009-01
Application #
8526053
Study Section
Special Emphasis Panel (ZRG1-F10B-S (20))
Program Officer
Williams, John
Project Start
2013-09-30
Project End
2017-09-29
Budget Start
2013-09-30
Budget End
2014-09-29
Support Year
1
Fiscal Year
2013
Total Cost
$43,251
Indirect Cost
Name
Case Western Reserve University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Mullin, Nathaniel K; Mallipeddi, Nikhil V; Hamburg-Shields, Emily et al. (2017) Wnt/?-catenin Signaling Pathway Regulates Specific lncRNAs That Impact Dermal Fibroblasts and Skin Fibrosis. Front Genet 8:183
Budnick, Isadore; Hamburg-Shields, Emily; Chen, Demeng et al. (2016) Defining the identity of mouse embryonic dermal fibroblasts. Genesis 54:415-30
Hamburg-Shields, Emily; DiNuoscio, Gregg J; Mullin, Nathaniel K et al. (2015) Sustained ?-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes. J Pathol 235:686-97