ENDOTHELIAL DYSFUNCTION AND THERAPUTIC TARGETS IN PULMONARY ARTERIAL HYPERTENSION
NATIONAL INSTITUTES OF HEALTH, BETHESDA, MD AND SURROUNDING AREA
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.
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.
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.
Qualifications: Applicants must have the following: Ph.D. degree in the Biological Sciences, conferred within the last five years, with an interest in translational research related to vascular biology and signal transduction. Qualified candidates should have direct experience with many of the following laboratory techniques: Cell culture, cell transfection, ELISA, Western blotting, electromobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, DNA cloning and subcloning, and site directed mutagenesis. Expertise in confocal microscopy and flow cytometry would be highly valued. The candidate is expected to conduct semi-independent research and function as part of a team. A strong background in cell signaling and molecular biology is required. Previous experience in vascular biology is highly desirable.
To Apply: Please send a cover letter, a CV including bibliography, and the names and contact information for three references to Robert Danner, MD, Senior Investigator, email@example.com.
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