Fibrosis is the development of excess extracellular matrix in an organ or tissue. It can occur as part of the reparative process or can be idiopathic in origin. Systemic sclerosis (SSc) or scleroderma is the prototypic idiopathic fibrosing disease. In addition, many other diseases such as pulmonary fibrosis, hepatic cirrhosis, and fibrosing congestive heart failure are also characterized by excess synthesis and deposition of extracellular matrix. These fibrotic diseases are influenced by many environmental and genetic factors and have been extensively studied. However, many of the basic mechanisms of disease pathogenesis remain elusive and as a consequence there are few effective therapies for the prevention of fibrosis. This application will study genetic factors that regulate fibrosis in dermal tissues using a mouse autoimmune disease model, called Tight Skin 2 (Tsk2). We gathered a strong team to tackle a long standing issue in the tsk2 mouse, the genetic basis of disease. The Tsk2 mouse has a mutation which causes phenotypic changes in its skin which are similar to the human autoimmune disease SSc. The Tsk2 mutation was first reported in 1986. The mutation appeared in the offspring of a male from the 101/H mouse strain as a result of administration of the mutagenic agent, ethylnitrosourea. Studies indicated that excess collagen production was the result of an increased number of collagen expressing cells as well as elevated collagen expression on a per cell basis, a characteristic of many fibrotic diseases. We will focus on the identification of the mutated gene in the disease locus of the Tsk2 mouse. The mutation has been localized to mouse chromosome 1 and considerable effort has been expended in the study of the molecular mechanisms of the disease, yet the genetic basis remains unknown and the causative mutation has not been identified. If successful, we will remove a significant bottleneck from the study of this important mouse model of fibrosis.

Public Health Relevance

Systemic sclerosis (SSc) or scleroderma is the prototypic idiopathic fibrosing disease. The origin of SSc is unknown but is believed to be the result of a combination of a genetic predisposition and undetermined environmental factors. This application will study genetic factors that regulate fibrosis in dermal tissues using a mouse autoimmune disease model, called Tight Skin 2 (Tsk2).

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000671-03
Application #
8597359
Study Section
Immunology A (IMMA)
Project Start
2011-10-01
Project End
2015-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Memphis VA Medical Center
Department
Type
DUNS #
078577285
City
Memphis
State
TN
Country
United States
Zip Code
38104