Research in the Ormiston Lab is focused on the cellular and molecular mechanisms by which circulating cells of the immune system influence vascular structure, growth and integrity. This work is centered on understanding the contribution of endothelial-immune interactions to the pathogenesis of pulmonary arterial hypertension (PAH) and other diseases of uncontrolled vascular remodeling.
PAH is a disease of occlusive vascular remodeling that is marked by immune dysfunction and the cancer-like proliferation of vascular endothelial and smooth muscle cells. As disease progresses, the formation of obstructive cellular lesions at the level of the pre-capillary arterioles leads to increased pulmonary vascular resistance, right ventricular hypertrophy and death by right heart failure. Current therapies for PAH alleviate symptoms, but are extremely expensive ($3.45 bn/yr globally) and only tangentially address the underlying drivers of disease progression. As a result, the annual mortality rate for this female-predominant syndrome remains high (~15%), in-line with stage 3 metastatic breast cancer.
PAH is strongly linked to immune dysfunction, both in the setting of autoimmune diseases, such as scleroderma and lupus, and viral infections, like HIV. Even PAH patients with no associated inflammatory conditions exhibit signs of altered immune function. Our work is focused on the contribution of Natural Killer (NK) cells to the pathogenesis of PAH. NK cells are traditionally viewed as the cytotoxic effector cells of innate immunity, charged with the identification and lysis of stressed, cancerous or virally infected cells. In addition to this basic functionality, there is a growing body of literature supporting a role for NK cells in the regulation of vascular remodeling.
Several reports have highlighted endothelial dysfunction, in the form of disordered angio-proliferation, increased vascular leak and an enhanced susceptibility to apoptosis, as an essential contributor to pathological vascular remodeling in PAH. Genetic evidence points to a loss of the type II bone morphogenetic protein receptor (BMPR-II) in the pulmonary endothelium as a critical factor in the initiation and progression of disease. We study how mutations in the gene encoding BMPR-II, which are found in roughly 20% of PAH patients, contribute to impaired endothelial-immune interactions in the pulmonary circulation.
This study uses patient samples and cultured NK cells to model and study the mechanisms that drive NK cell impairment in PAH. Mass cytometry techniques are used to analyze up to 40 protein markers at a single-cell level
This project uses NK-specific knockout mouse models to identify and study the mechanisms driving observed changes in NK cell number, phenotype and function in PAH
This project uses PAH patient endothelial cells, siRNA silencing and endothelial-specific knockout mouse models to examine the impact of BMPR-II deletion or mutation on the response of the pulmonary endothelium to stimulation with the BMPR-II ligand, BMP-9.
This project examines the impact of BMPR-II loss on NK cell proliferation, phenotype and function. Work will capitalize on both cell culture techniques and genetic mouse models of PAH
This project will use endothelial-conditional knockout mice to study tumor vascularization in the context of partial or full BMPR-II loss.
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