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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1-MLB)
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Boston University
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