Sine Oculis Homeobox Homolog 1 and clusterin in Pulmonary Hypertension associated with Systemic Sclerosis

Abstract / Project Summary: Systemic sclerosis (SSc) is a heterogenous autoimmune disease that disproportionately affects African American women. The etiology of SSc is not fully understood, a subset of patients develops pulmonary hypertension (PH), a fatal disease that is characterized by a mean pulmonary arterial pressure (mPAP) of 20 mmHg at rest. PH in SSc can happen on its own, termed SSc-PAH or in combination with interstitial lung disease (ILD), a common complication in SSc that is characterized by fibrotic deposition. Hallmarks of PH include vascular remodeling and right-ventricle (RV) dysfunction. Despite advances in care for PH, many patients with PH including those with SSc, require lung transplantation for survival, despite the dire 5-year survival rate of this procedure. This underscores the need to identify new treatments for SSc-PH. A hallmark of PH is vascular remodeling, a complex process that involves injury to endothelial cells and subsequent proliferation of both the endothelial and smooth muscle layer of the vasculature. Changes in cell metabolism, and activation of de-differentiation pathways have been reported to play an important pathophysiological role in vascular remodeling. Exciting preliminary results from our group have revealed increased expression of the developmental transcription factor: Sine Oculis Homeobox Homolog 1 (SIX1) in remodeled vessels from patients with SSc-PH. These results are significant since SIX1 is known to promote cell proliferation and differentiation. Our group has demonstrated that SIX1 plays a role in lung fibrosis by stimulating the expression of clusterin (CLU), a mediator that is associated with SSc and PH, where it may promote autophagy. Several isoforms of CLU exist through alternative splicing including secreted (s) CLU. Thus, the aim of our study is to determine the expression levels of SIX1 and its co-factors: eyes absent (EYA1) and EYA2 as well as downstream target sCLU in pulmonary artery smooth muscle cells (PASMC) from patients with SSc- PH. We will then evaluate the mechanisms that are activated in SSc derived PASMC following treatment with exogenous sCLU and evaluate signaling pathways that promote autophagy and cell proliferation. Next, using SIX1 loss of function mice, we aim to uncover the role of SIX1 in an experimental model of PH.