The overall goal of our research is to understand the molecular mechanisms that underlie pathologic manifestations of scleroderma (SSc). Although etiology of SSc is still poorly understood, there is increasing evidence that inflammation directly contributes to the pathological vascular remodeling in SSc-associated pulmonary hypertension (SSc-PAH) and likely also plays a role in other complications. Published literature indicates that signaling pathways induced by endoplasmic reticulum (ER) stress and unfolded protein response (UPR) can initiate and propagate inflammation. We observed a significant increase of ER stress/UPR markers, which correlated with increase of inflammatory mediators (IL-6) in peripheral blood mononuclear cells (PBMCs) obtained from SSc-PAH patients. We have also noted that presence of HLAB35, which is associated with increased risk of PAH, induces ER stress/UPR in cultured endothelial cells, and correlates with elevated levels of ER strss/UPR markers in patient PBMCs. Furthermore, an ongoing study has revealed that in endothelial cells HLA-B35 synergizes with selected TLR (Toll-like receptor) agonists in upregulation of inflammatory cytokines and chemokines. Based on these novel observations we propose the following hypothesis: ER stress and UPR play a pathogenic role in SSc-PAH by sensitizing endothelial and immune cells to TLR agonists resulting in exacerbation of inflammatory responses. HLA-B35 may further intensify the disease process by contributing to endothelial cell dysfunction, as well as to activation of immune system in patients with PAH. To test these hypotheses and to gain additional insights into the molecular pathways underlying SSc-PAH, we propose the following specific aims.
Aim 1 : To determine the role of ER stress/UPR and HLA-B35 in endothelial cell function.
Aim 2 : To determine the role of ER stress/UPR and HLA-B35 in activation of immune cells.
Aim 3 : To determine the prevalence of HLAB35 allele and to perform genetic analyses of ER stress/UPR genes in IcSSc.
This study will lead to new knowledge on the vascular and immune mechanisms contributing to pulmonary hypertension in patients with SSc. Furthermore, these studies may result in characterization of novel disease markers and genetic associations, and ultimatily may provide logical targets for therapeutic interventions.
|Grzegorzewska, Agnieszka P; Seta, Francesca; Han, Rong et al. (2017) Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7:41605|
|Makino, Katsunari; Makino, Tomoko; Stawski, Lukasz et al. (2017) Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis. J Invest Dermatol 137:1671-1681|
|Fleury, Michelle; Belkina, Anna C; Proctor, Elizabeth A et al. (2017) Increased expression and modulated regulatory activity of co-inhibitory receptors PD-1, TIGIT and TIM-3 in lymphocytes of systemic sclerosis patients. Arthritis Rheumatol :|
|Lafyatis, Robert; Mantero, Julio C; Gordon, Jessica et al. (2017) Inhibition of ?-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82. J Invest Dermatol 137:2473-2483|
|Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi et al. (2017) Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. J Invest Dermatol 137:631-640|
|Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor et al. (2017) A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med 9:27|
|Nazari, Banafsheh; Rice, Lisa M; Stifano, Giuseppina et al. (2016) Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90. Am J Pathol 186:2650-64|
|Rice, Lisa M; Stifano, Giuseppina; Ziemek, Jessica et al. (2016) Local skin gene expression reflects both local and systemic skin disease in patients with systemic sclerosis. Rheumatology (Oxford) 55:377-9|
|Martyanov, Viktor; Whitfield, Michael L (2016) Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data. Curr Opin Rheumatol 28:83-8|
|Ziemek, Jessica; Man, Ada; Hinchcliff, Monique et al. (2016) The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis. Rheumatology (Oxford) 55:911-7|
Showing the most recent 10 out of 59 publications