PHA/AHA Post Doctoral Fellowship Award Winner Winner 2006

Michelle Beutz, MD Michelle Beutz, MD

Sponsor: University of Colorado at Denver and Health Sciences Center, CO
"Sphingosine-1-Phosphate and Hypoxic Pulmonary Hypertension"
Term: July 1, 2006 – June 30, 2008

Summary of Research Project:

Sphingosine-1-Phosphate and Hypoxic Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is an often lethal disease characterized by an increase in pulmonary vascular resistance which can lead to right heart failure. As the population ages, increasing numbers of patients are developing PAH in the setting of lung disease and chronic hypoxemia. COPD is the most common cause of hypoxia-related PAH, but this form of PAH also occurs in individuals who reside at high altitude or have interstitial lung disease, alveolar hypoventilation syndromes, or sleep disordered breathing.

PAH is thought to be the result of both sustained vasoconstriction and arterial structural remodeling in the pulmonary vessels. Sustained hypoxic vasoconstriction is poorly understood and there are currently no available therapies targeted at this cause of pulmonary hypertension.

Our laboratory has published evidence that sustained vasoconstriction of the pulmonary vasculature occurs through a signaling pathway involving activation of a small G protein known as RhoA, and its associated enzyme, Rho-kinase. Inhibition of RhoA/Rho-kinase signaling nearly reverses elevated PVR in chronically hypoxic rats. What is not known, however, is what signaling molecule is responsible for activating the RhoA/Rho-kinase pathway. We believe sphingosine-1-phosphate (S1P), a bioactive phospholipid released from activated platelets, may be one important activator of the RhoA/Rho-kinase pathway.

Microthrombi are a common pathologic finding in PAH. Hypoxia is known to activate platelets. Activated platelets, in turn, release abundant amounts of S1P. S1P further activates platelets. Thus, S1P can reach high concentrations in the pulmonary microvasculature. S1P has been shown to cause both vasodilatation and vasoconstriction, with differing effects in differing vascular beds. Our preliminary evidence demonstrates S1P is a potent vasoconstrictor of pulmonary vessels. Its effects are even more potent in pulmonary vessels exposed to chronic hypoxia.

In summary, we believe we have identified a novel vasoconstrictor of the pulmonary vasculature which is released by activated platelets and contributes to sustained vasoconstriction in PAH, particularly in PAH secondary to chronic hypoxia.

Biography


Dr. Michelle Beutz is a native of Evergreen, Colorado. She attended medical school at Washington University in St. Louis, MO. As a second year medical student, Dr. Beutz remembered learning about pulmonary hypertension when she studied the lungs and how this incited great interest in the illness. As she learned more about pulmonary hypertension, she saw an opportunity to focus on the illness in her research. Her current research at the University of Colorado Health Science Center in Denver is on the “Sphingosine-1-Phosphate and Hypoxic Pulmonary Hypertension” which mainly focuses on secondary forms of pulmonary hypertension. Through this research, she hopes to “define the basic mechanisms by which S1P (a platelet-released signaling molecule) causes pulmonary hypertension”. Dr. Beutz is also hoping to discover something that may provide therapeutic options that benefit people with chronic hypoxic pulmonary hypertension because the options are limited currently for those individuals.

Though Dr. Beutz finds herself busy with her research and upcoming publications on pulmonary hypertension, she still finds spare time to hike and enjoys getting together with friends to cook in a supper club. Dr. Beutz’ future career goals are to continue to be a clinician and a researcher. “I really enjoy being in the clinic and seeing patients and seeing how what you do in the lab might cross over for patients”.


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