The objective of our original grant application was to identify the gene underlying the spontaneous, autosomal, recessive mouse mutation named """"""""chronic proliferative dermatitis"""""""" (original mutant locus symbol: cpdm). This was accomplished and identified as Sharpin. The function of the mutated Sharpin gene, responsible for the cpdm phenotype, is poorly understood. Mice carrying spontaneous mutations in Sharpin reveal that it plays a key role in normal development of secondary lymphoid organs and its absence leads to eosinophilia with accumulations of eosinophils and other inflammatory cells in parenchymous organs. These mutant mice develop a severe psoriasiform skin disease characterized by persistent, marked, epidermal hyperplasia, accompanied by apoptotic keratinocytes, accumulation of eosinophils, and concurrent increases in cutaneous mast cells, macrophages, and other inflammatory cells. Inflammatory changes are also evident in other organs including joints, lungs, upper gastrointestinal tract, and liver. Experiments proposed here will define the function of Sharpin and determine how this gene modulates normal immune system development, and controls inflammation in the skin and other organs. We will utilize gene arrays and network analysis software in time course studies to determine the molecular events involved. Crossing a floxed Sharpin transgenic mouse with various promoter-Cre recombinase genetically engineered mice available in our repository will allow us to determine the effects of ubiquitous and organ- or cell-specific inactivation of Sharpin. Cell transfection studies and chlP-on-chip approaches will identify targets allowing us to determine in which gene/protein networks Sharpin functions. These approaches will define the temporal pathogenesis of skin and immune system abnormalities due to inactivation of the Sharpin gene and determine in which molecular pathway(s) this gene functions. The chronic proliferative dermatitis mutant mouse is a valuable tool to define what appears to be a novel disease mechanism for immune system development and psoriasiform dermatitis. Relevance to Public Health: We identified a gene that when mutated, results in severe systemic inflammatory disease that shares pathologic changes with several human diseases. We will define the molecular pathogenesis of the mouse disease. It is likely that a homologous condition exists in humans and knowledge learned from the mouse model will aid in diagnostic test and therapy development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049288-06
Application #
7813833
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2002-12-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2010
Total Cost
$380,474
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Potter, Christopher S; Silva, Kathleen A; Kennedy, Victoria E et al. (2017) Loss of FAS/FASL signalling does not reduce apoptosis in Sharpin null mice. Exp Dermatol 26:820-822
Peuhu, Emilia; Kaukonen, Riina; Lerche, Martina et al. (2017) SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. EMBO J 36:165-182
Hosur, Vishnu; Burzenski, Lisa M; Stearns, Timothy M et al. (2017) Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing. Exp Mol Pathol 102:337-346
Ward, Jerrold M; Schofield, Paul N; Sundberg, John P (2017) Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail. Lab Anim (NY) 46:146-151
HogenEsch, Harm; Sola, Mario; Stearns, Timothy M et al. (2016) Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis. Exp Mol Pathol 101:303-307
Sundberg, John P; Silva, Kathleen A; King Jr, Lloyd E et al. (2016) Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening. Methods Mol Biol 1438:199-224
Sundberg, John P; Dadras, Soheil S; Silva, Kathleen A et al. (2015) Excavating the Genome: Large-Scale Mutagenesis Screening for the Discovery of New Mouse Models. J Investig Dermatol Symp Proc 17:27-9
Sundberg, John P; McElwee, Kevin; Brehm, Michael A et al. (2015) Animal Models for Alopecia Areata: What and Where? J Investig Dermatol Symp Proc 17:23-6
Chien, Syu-Jhe; Silva, Kathleen A; Kennedy, Victoria E et al. (2015) The pathogenesis of chronic eosinophilic esophagitis in SHARPIN-deficient mice. Exp Mol Pathol 99:460-7
Potter, Christopher S; Wang, Zhe; Silva, Kathleen A et al. (2014) Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. PLoS One 9:e85666

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