Systemic sclerosis (SSc) is a complex and clinically heterogeneous disease characterized by synchronous fibrosis that simultaneously affects multiple organs. The myofibroblast, an activated contractile mesenchymal cell, is the main culprit in the pathogenesis of all forms of fibrosis. However, there is a gap in understanding how myofibroblast became activated and stay activated in SSc, hindering development of effective treatment. The objective of this SF proposal is to capitalize on our recent discoveries implicating primary cilia in the pathogenesis of fibrosis in SSc. Using unbiased RNAseq technology, we found that expression of a little-known gene called SPAG17 was markedly reduced in SSc. Our team showed that SPAG17 regulates both the length and function of primary cilia, which are essential cellular antennae essential for morphogen (hedgehog, Wnt, TGF-ß) signaling. Mesenchymal cells lacking SPAG17 form stunted cilia, and demonstrate constitutive profibrotic activity. Notably, while SPAG17-null mice are viable, they develop spontaneous fibrosis in the skin, muscle and multiple organs, and therefore represent an unprecedented model for spontaneous multi-organ fibrosis. The premise of this proposal is that SPAG17 controls both ciliogenesis and fibrogenesis, and reduced SPAG17 expression in SSc will result in ciliary disfunction that leads to aberrant morphogen signaling and multiple organ fibrosis. We will test this novel premise in two aims: Aim 1 will characterize the cell types driving fibrosis by examining fibrosis in cell-type specific SPAG17 KO mice. Aim 2 will determine whether fibrosis-driven phenotype associated with loss of SPAG17 is mediated by disrupted primary cilia in both humans and in murine models. This aim will use cutting-age super-high resolution microscopy technology in combination of molecular cell biology techniques, and several pharmacologic compounds to dissect the mechanistic pathway underlying myofibroblast activation and fibrosis associated with loss of SPAG17 and cilia disfunction. Our proposal is highly innovative, since SPAG17 expression, mechanism and role in fibrosis has never been studied, and the contribution of cilia to disease pathology in SSc is completely unknown. Significance lies in the potential to define a novel role for SPAG17, ciliogenesis and ciliary signaling as fundamental mechanisms driving SSc. Because our investigative team has deep expertise and unique experimental tools in both fibrosis and ciliogenesis, we are poised for successful achievement of our aims. Understanding the contribution of SPAG17 and cilia in fibrosis will ultimately inform the development of entirely new approaches for fibrosis therapy.
|Effective start/end date||4/1/19 → 8/31/20|
- Virginia Commonwealth University (FP00009210_SA001//Agmt 3/12/19)
- Scleroderma Foundation (FP00009210_SA001//Agmt 3/12/19)