Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease with poor clinical outcome. The progress of the disease is characterized by pulmonary vascular remodelling, increases in pulmonary artery pressure, and right heart failure. Our research group has investigated the resistin family of proteins in PAH and demonstrated pro-inflammatory and proliferative actions, their ability to induce PAH in rodent models, and that the two human correlate proteins are upregulated in human PAH lung and peripheral blood in correlation with severity of hemodynamic changes of PAH, suggesting potential etiologic as well as biomarker properties. Inhibition of this pathway in rodents prevents the development of hypoxia-induced PAH. We propose to develop and initiate pre-clinical testing of specific agents to inhibit the onset or progression of PAH in humans by inhibiting the action of the two human resistin-family isoforms: Resistin and Resistin-like molecule beta (RELMP). We suggest (1) targeting resistin and RELMp by monoclonal antibodies, (2) inhibiting their expression by siRNA, and (3) High throughput screening for small inhibitory molecules to be used as therapeutic approaches to alter the course of PAH. We will investigate these potential therapies in a murine model of vascular growth and verify their suitability for human treatment through in vitro models using human cells. We anticipate that a successful treatment may, alone or in combination with other approaches, delay or even arrest disease progression, and thus significantly benefit patient sun/ival.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease with poor clinical outcome and we have discovered a new pathway that can cause PAH. This proposal seeks to develop drugs and biomarkers that target this pathway to create new treatments for PAH

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL107182-02
Application #
8263754
Study Section
Special Emphasis Panel (ZHL1-CSR-D (F1))
Program Officer
Moore, Timothy M
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$490,962
Indirect Cost
$191,595
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yamaji-Kegan, Kazuyo; Takimoto, Eiki; Zhang, Ailan et al. (2014) Hypoxia-induced mitogenic factor (FIZZ1/RELM?) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 306:L1090-103
Kolosova, Irina A; Angelini, Daniel; Fan, Chunling et al. (2013) Resistin-like molecule ýý stimulates proliferation of mesenchymal stem cells while maintaining their multipotency. Stem Cells Dev 22:239-47
Fan, Chunling; Johns, Brian A; Su, Qingning et al. (2013) Choosing the right antibody for resistin-like molecule (RELM/FIZZ) family members. Histochem Cell Biol 139:605-13