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 #
5I01BX000671-02
Application #
8391578
Study Section
Immunology A (IMMA)
Project Start
2011-10-01
Project End
2015-09-30
Budget Start
2012-10-01
Budget End
2013-09-30
Support Year
2
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Memphis VA Medical Center
Department
Type
DUNS #
078577285
City
Memphis
State
TN
Country
United States
Zip Code
38104
Cui, Jinglin; Li, Jing; Lu, Hang et al. (2018) Data sets of eQTL loci, correlation analysis, and overlapped genes among gene sets that their expression levels are closely related to genes of Vegf family. Data Brief 20:1854-1860
Cui, J; Sun, D; Lu, H et al. (2018) Comparison of effectiveness and safety between conbercept and ranibizumab for treatment of neovascular age-related macular degeneration. A retrospective case-controlled non-inferiority multiple center study. Eye (Lond) 32:391-399
Liu, Fengxia; Jiao, Yan; Jiao, Yun et al. (2016) Sex difference in EGFR pathways in mouse kidney-potential impact on the immune system. BMC Genet 17:146
Liu, Xiaoyun; Jiao, Yan; Cao, Yanhong et al. (2016) Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease in mice deficiency of IL-1RA. BMC Immunol 17:25
Jiao, Yan; Chen, Hong; Gu, Tianshu et al. (2015) Molecular network of important genes for systemic sclerosis-related progressive lung fibrosis. BMC Res Notes 8:544
Pattanaik, Debendra; Brown, Monica; Postlethwaite, Bradley C et al. (2015) Pathogenesis of Systemic Sclerosis. Front Immunol 6:272
Wang, Lishi; Liu, Hongchao; Jiao, Yan et al. (2015) Differences between Mice and Humans in Regulation and the Molecular Network of Collagen, Type III, Alpha-1 at the Gene Expression Level: Obstacles that Translational Research Must Overcome. Int J Mol Sci 16:15031-56
Zhang, Yueying; Huang, Jinsong; Jiao, Yan et al. (2015) Bone morphology in 46 BXD recombinant inbred strains and femur-tibia correlation. ScientificWorldJournal 2015:728278
Deng, Nan; Jiao, Yan; Cao, Yanhong et al. (2014) Genomic locus on chromosome 1 regulates susceptibility to spontaneous arthritis in mice deficiency of IL-1RA. BMC Immunol 15:57