ENDOTHELIAL DYSFUNCTION IN PULMONARY ARTERIAL HYPERTENSION
CLINICAL RESEARCH CENTER, BETHESDA, MD AND SURROUNDING AREA
Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility and 2) triggering stimuli that initiate pulmonary vascular inflammation, injury and pathologic remodeling play a central role in the pathogenesis and progression of PAH. Loss-of-function mutations in bone morphogenetic protein receptor-2 (BMPR2), a member of the TGF-β superfamily, are the most common cause of heritable PAH. BMPR2 silencing in human pulmonary artery endothelial cells reproduced 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 can be used to develop a comprehensive picture of pathogenic mechanisms and therapeutic targets. The comparative biology of these seemingly unrelated genetic defects, under both homeostatic and stress conditions (i.e. hypoxia, and iron deficiency), may lead to both individualized and possibly universal approaches for arresting or even reversing pathologic vascular remodeling in PAH.
Laboratory: In addition to a full complement of standard molecular biology equipment 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 CO gas tensions to within 1 ppm over a 0-1000 ppm range, and; 3) control of normobaric •NO tensions in two chambers to within 1 ppm over a 0-300 ppm range.
A rat animal model of PAH is being developed for the preclinical testing of therapeutic approaches arising from the basic science laboratory. An active clinical research program in PAH also provides access to patient samples and a pathway for future clinical trials.
Applicants must have the following:
- Ph.D. degree in the Biological Sciences with an interest in translational research related to vascular biology and signal transduction.
- Less than 5 years of research experience since receipt of the doctoral degree.
- Direct experience with many of the following laboratory techniques: Cell culture, cell transfection, ELISA and 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 ability 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.
Please send a cover letter, a CV including bibliography, and the names and contact information for three references to Robert Danner, MD, Senior Investigator, firstname.lastname@example.org.
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