30 July 2018

Post-doc position at the NIH


Position Description:

Pulmonary arterial hypertension (PAH) is a rare, female predominant, progressive disease characterized by endothelial and smooth muscle cell proliferation, and pulmonary vascular remodeling with distal vessel pruning. Reduction in pulmonary vascular cross-sectional area leads to a progressive increase in pulmonary vascular resistance that eventually overwhelms right ventricular (RV) adaptation, resulting in RV failure and ultimately death. Prior to recent advances in treatment, the median survival was only 2.8 years. With the advent of semi-selective pulmonary vasodilator therapy, outcomes for PAH patients have improved, but current therapy is not curative and mortality remains unacceptably high.

Heterozygous, loss-of-function (LOF) germline mutations in bone morphogenetic protein type II receptor (BMPR2) are the most common genetic cause of PAH accounting for 70% of familial cases and 10-40% of idiopathic PAH. BMPR2 expression is markedly reduced in end-stage PAH, even in patients not harboring mutations. Importantly, BMPR2 silencing in human pulmonary artery endothelial cells reproduces many of the phenotypic abnormalities associated with PAH in vivo, including proliferation, hyper-motility and a disrupted cytoskeletal architecture.

Endothelial cells with molecular defects in various PAH-associated genes such as BMPR2, CAV1 and SMAD8/9 are being used to develop a more complete picture of pathogenic mechanisms and therapeutic targets. The comparative biology of these loosely-related genetic defects implicate overlapping networks that drive PAH pathobiology including inflammation (JAK/STAT, interferon), oncogenic pathways (Ras/Raf/MEK/ERK, PI3K/AKT), pseudohypoxia (PHD2, HIF2alpha, SIRT1), endothelial to mesenchymal transition, and mitochondrial dysfunction. New approaches targeting these mechanisms at points of convergence have the potential to arrest or even reverse pathologic vascular remodeling in PAH.

In addition to a full complement of standard molecular biology equipment, flow cytometry, cell sorter and a microarray facility, the laboratory also has a custom-built state of-the-art incubator system (OXYCYCLER model CT82 -O2/CO2/CO/NO Profile Cell Culture System; Biospherix LTD, Lacona, NY). Unique features of this incubator include: 1) control of normobaric O2 tensions from 0.1-99.9% in all four chambers but independently in each; 2) control of normobaric carbon monoxide gas tensions to within 1 ppm over a 0-1000 ppm range, and; 3) control of normobaric nitric oxide tensions in two chambers to within 1 ppm over a 0-300 ppm range.

The SU-5416/hypoxia rat model of PAH model of PAH is available for the preclinical testing of therapeutic approaches arising from the basic science laboratory. An active clinical research program in PAH within the department also provides access to patient samples and a pathway for future clinical trials.

Resources are further enhanced by ongoing collaborations with other NIH laboratories and industry partners.

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