Targeting resitin and RELM-beta to treat pulmonary hypertension

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DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions): 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