Project 3

The Role of ER Stress in Systemic Sclerosis

PI – Maria Trojanowska, PhD

Project 3 will focus on the role of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) in the pathological vascular remodeling in SSc-associated pulmonary hypertension (SSc-PAH). We will also explore the specific role of HLA-B35 (an MHC class I antigen associated with increased risk of SSc-PAH) in inducing ER stress and UPR in endothelial and immune cells. The proposal is based on novel observations that demonstrate that the presence of HLA-B35 induces ER stress/UPR in cultured endothelial cells and correlates with elevated levels of ER stress/UPR markers in PBMCs from SSc-PAH. Furthermore, HLA-B35 synergizes with selected TLR agonists in upregulation of inflammatory cytokines and chemokines. Based on these 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. These hypotheses will be tested using two approaches: i) in vitro cell experiments to gain additional insights into the molecular pathways underlying SSc-PAH, ii) extensive analyses of patient PBMCs and skin biopsies for the presence of ER stress/UPR markers conducted in collaboration with Project 1 (Lafyatis) and Project 2 (Farber).

This study will lead to new knowledge on the vascular and immune mechanisms contributing to pulmonary hypertension in patients with SSc, as well as characterization of novel disease markers and genetic associations, and ultimatily may provide logical targets for therapeutic interventions.