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ARRA Investments in Pulmonary Hypertension (PH)

Public Health Burden
PH is an irreversible, malignant elevation of pulmonary vascular pressures that causes death due to failure of the right side of the heart.  Although idiopathic pulmonary hypertension is considered a rare disease, its true epidemiology is being called into question because of an increasing awareness that PH may occur in the setting of more prevalent respiratory diseases such as COPD, that it can develop in systemic diseases such as sickle cell anemia, and that right-heart dysfunction may actually occur earlier in the disease pathogenesis than previously recognized.  The annual number of hospitalizations attributable to PH in the United States rose significantly from 1980 to 2000, especially for women, and worldwide estimates of all-cause PH are increasing.

Within the past few years, drugs to dilate the vasculature have become available for use in PH.  Current therapies modestly extend survival but do not lead to regression or cure, and no clear indicators of therapeutic efficacy, such as surrogate markers, have been identified.  The sole alternative when medical therapy fails is lung transplantation, and it extends survival only minimally.  ARRA funds are supporting projects to:
  • Identify new ways to direct current vasodilatory therapeutics to the pulmonary vasculature using stem cell-based drug delivery.1
  • Use stem cell-based drug delivery methods to test newly identified interventional targets.2
  • Design biologic delivery vectors to provide stable and selective production of therapeutic gene products in the pulmonary vasculature.3
  • Use cell-specific diagnostic imaging to deliver disease-modifying drugs directly to relevant pulmonary vascular lesions.4
  • Identify biomarkers of treatment response that can guide therapeutic decision-making in pediatric patients suffering from idiopathic PH. 5
  • Test new devices for acute right-ventricular support during periods of critically elevated pulmonary vascular pressures that cause right-ventricular failure.6
PH Disease Pathogenesis
As understanding of PH has evolved, new hypotheses have been proposed that better describe its development.  ARRA-funded projects include research to:
  • Determine the relationship between innate or adaptive immune responses and the development of pulmonary vascular disease.7 8
  • Delineate the pathophysiologic and genetic factors specific to the heart that may contribute to the development of integrated pulmonary vascular–right-heart disease.9
  • Study the ultrastructural and intracellular components of phenotypes that are abnormal or become impaired in function during the development of PH.10 11
  • Probe the biologic reasons why more women than men develop PH 12
Pulmonary Vascular Biology
While PH is well-known as originating within the pulmonary vascular–right-heart axis, it has become increasingly apparent from PH studies that our fundamental knowledge of the pulmonary vasculature is incomplete.  ARRA funding is supporting important basic and translational investigations in pulmonary vascular biology to:
  • Examine the critical roles of oxygen and oxygen deficiency in pulmonary vascular smooth muscle function.13
  • Explore the mechanisms by which other oxygen-based compounds, such as carbon monoxide and nitric oxide, regulate lung cell function during normal physiology, injury, and repair of vascular damage.14 15
  • Define the unique characteristics of the cells lining the vascular surface in relation to function and location along the pulmonary vascular bed 16 and uncover critical signals needed for lung endothelial cells to form healthy physiological barriers.17

  1. 1RC1HL100807-01 -- Prostacyclin-secreting Cells as Therapy for Pulmonary Artery Hypertension -- Dixon, Richard (TX)
  2. 1RC1HL099980-01 -- ACE2 as a Target for Pulmonary Hypertension Therapeutics -- Raizada, Mohan and Grant, Maria (FL)
  3. 1R01HL092941-01A1 -- Development of Double-targeted Vectors for Long-term Vascular Expression in vivo -- Curiel, David (AL)
  4. 1RC1HL100849-01 -- Zipcode Based Nano-imaging of Hypertensive Pulmonary Arteries -- Tuder, Rubin (CO)
  5. 1RC1HL099786-01 -- Quantifiable Biomarkers of Vasodilator Therapeutic Response in Children with IPAH -- Everett, Allen (MD)
  6. 1RC1HL100585-01 -- Minimally Invasive VAD for Treatment of Acute Right Heart Failure -- Corbett, Scott (MA)
  7. 3R01HL082662-03S1 -- An Autoimmune Basis for Pulmonary Hypertension -- Nicholls, Mark (CA)
  8. 1R21HL092370-01A2 -- Muscularization of Pulmonary Arteries Induced by an Adaptive Immune Response -- Grunig, Gabriele (NY)
  9. 3P50HL084946-03S1 -- Molecular Determinants of Pulmonary Arterial Hypertension -- Hassoun, Paul (MD)
  10. 3R01HL086939-03S1 -- Vascular Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension -- Chesler, Naomi (WI)
  11. 1RC1HL099462-01 -- Impaired Mitochondrial Fusion in Pulmonary Arterial Hypertension -- Archer, Stephen (IL)
  12. 1R21HL093181-01A1 -- Role of 15-lipoxygenase in Enhanced Pulmonary Vasoconstriction in Females -- Pfister, Sandra (WI)
  13. 2R01HL067191-05A2 -- Chronic Hypoxia and Pulmonary Vascular Smooth Muscle -- Shimoda, Larissa (MD)
  14. 2R01HL060234-10A1 -- Heme oxygenase1/Carbon Monoxide in Lung Vascular Injury -- Choi, Augustine (MA)
  15. 3R01HL060917-10S1 -- Nitric Oxide Production and Reactions in the Lung -- Erzurum, Serpil (OH)
  16. 3P01HL066299-08S1 -- Lung Endothelial Cell Phenotypes -- Stevens, Troy (AL)
  17. 3R01HL088328-03S1 -- Natriuretic Peptides in Pulmonary Endothelial Cell Barrier Function -- Klinger, James (RI)

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