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.
Treatment
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
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1. 1RC1 HL100807-01 Prostacyclin-secreting Cells as Therapy for Pulmonary Artery Hypertension – Dixon, Richard (TX)
2. 1RC1 HL099980-01 ACE2 as a Target for Pulmonary Hypertension Therapeutics – Raizada, Mohan and Grant, Maria (FL)
3. 1R01 HL092941-01A1 Development of Double-targeted Vectors for Long-term Vascular Expression in vivo – Curiel, David (AL)
4. 1RC1 HL100849-01 Zipcode Based Nano-imaging of Hypertensive Pulmonary Arteries – Tuder, Rubin (CO)
5. 1RC1 HL099786-01 Quantifiable Biomarkers of Vasodilator Therapeutic Response in Children with IPAH – Everett, Allen (MD)
6. 1 RC1 HL100585-01 Minimally Invasive VAD for Treatment of Acute Right Heart Failure – Corbett, Scott (MA)
7. 3 R01 HL082662-03S1 An Autoimmune Basis for Pulmonary Hypertension – Nicholls, Mark (CA)
8. 1 R21 HL092370-01A2 Muscularization of Pulmonary Arteries Induced by an Adaptive Immune Response – Grunig, Gabriele (NY)
9. 3 P50 HL084946-03S1 Molecular Determinants of Pulmonary Arterial Hypertension – Hassoun, Paul (MD)
10. 3 R01 HL086939-03S1 Vascular Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension – Chesler, Naomi (WI)
11. 1 RC1 HL099462-01 Impaired Mitochondrial Fusion in Pulmonary Arterial Hypertension – Archer, Stephen (IL)
12. 1 R21 HL093181-01A1 Role of 15-lipoxygenase in Enhanced Pulmonary Vasoconstriction in Females – Pfister, Sandra (WI)
13. 2 R01 HL067191-05A2 Chronic Hypoxia and Pulmonary Vascular Smooth Muscle – Shimoda, Larissa (MD)
14. 2 R01 HL060234-10A1 Heme oxygenase1/Carbon Monoxide in Lung Vascular Injury – Choi, Augustine (MA)
15. 3 R01 HL060917-10S1 Nitric Oxide Production and Reactions in the Lung – Erzurum, Serpil (OH)
16. 3 P01 HL066299-08S1 Lung Endothelial Cell Phenotypes – Stevens, Troy (AL)
17. 3 R01 HL088328-03S1 Natriuretic Peptides in Pulmonary Endothelial Cell Barrier Function – Klinger, James (RI)
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