This application addresses the Challenge Area 06 of "Enabling Technologies and Prevention" and the specific Challenge Topic 06-HL-104 of "enabling technologies involving the development of nanotools for pulmonary medicine, particularly aimed at safer and more effective administration of life-prolonging drugs such as prostacyclines for pulmonary arterial hypertension". Severe pulmonary hypertension (SPH) is an irreversible, malignant elevation of pulmonary artery pressures, often associated with high mortality due to right side heart failure. The disease is characterized by complex pulmonary vascular lesions, including plexiform lesions due to endothelial cell proliferation. The current therapies, including prostacyclin and phosphodiesterase inhibitors extend survival, yet do not lead to regression or cure of the disease. Moreover, SPH is diagnosed at a late stage by invasive hemodynamic assessment of pulmonary artery pressures, which has been implemented more than a half a century ago. The most important challenges in SPH are overcoming the lack of early diagnostic tools, lack of noninvasive methods to monitor pulmonary vascular responses to potential systemic therapies, and the inability to deliver disease-modifying drugs directly to the relevant pulmonary vascular lesions. Given the unique phenotypic characteristics of endothelial cells in hypertensive pulmonary vascular lesions, we propose to discover peptide/receptor pairs that will permit the development of nanodevices for diagnostic pulmonary vascular imaging in SPH. We hypothesize that pulmonary vascular endothelial-cells harbor unique molecular markers that provide a specific molecular "zip" code defined by phage display screen of binding peptides. These peptides can be used for cell specific diagnostic imaging using molecular nanoplatforms with phage-nanogold or nano-gold peptide devices. Specific Aim 1 will define endothelial cell ligand/receptor pairs associated with SPH. Specific Aim 2 will formulate SPH-specific nanogold platforms of targeting phages or peptides discovered in Aim 1 for diagnostic imagining of pulmonary vascular lesions in SPH. The proposal relies on a comprehensive and multidisciplinary approach using normal and diseased human lung tissue of patients with SPH, relevant cell cultures, animal modeling, and state of the art phage display methodologies targeted at the pulmonary vasculature. To accomplish these goals, we have assembled an interdisciplinary team with expertise in SPH pathobiology and relevant model systems (Tuder and Erzurum), phage display methodology and gold phage-nanodevice assembly (Pasqualini/Arap), nanodevice assembly and chemistry (Boyes), and in vivo optical, computed tomography, and magnetic resonance imaging (Serkova). Our studies may provide expertise that can be extended to the development of disease-specific delivery of drugs mechanistically targeted to pulmonary vascular lesions, tailored imaging to different forms of pulmonary hypertension, and potential for biomarker discovery.

PUBLIC HEALTH RELEVANCE: Pulmonary hypertension is a severe disease caused by an increase in pressure in the blood vessels that carry blood from the right side of the heart to the lungs. Pulmonary hypertension can happen as an isolated condition, also called idiopathic pulmonary arterial hypertension, or as a complication of auto-immune diseases or other forms of lung disease. When present, it carries a bad prognosis. The main challenge in the field of pulmonary hypertension is the ability to diagnose the disease without having to put a probe into the patients'heart, ideally using imaging (i.e. x-Ray) of the affected pulmonary blood vessels. If accomplished, the diagnosis based on lung vascular imaging can be used to monitor patients treated with medications. Our approach uses a virus called phage to find unique "zip" addresses that can allow a molecule to find the diseased pulmonary blood vessels in pulmonary hypertension. We plan to make nanodevices (nano refers to the fact that these devices are very small, in the range of a hundredth of the thickness of human hair). These devices will then travel to the affected pulmonary vessels and allow us to use imagining tools to visualize the diseased vessels. Our research relies on a first stage of discovery of these zip codes and then builds these devices to be tested in human cells grown in a dish and in rats with a disease similar to that in humans. We can also use these devices to deliver drugs only to diseased cells and to build devices that can diagnose specific forms of pulmonary hypertension, such as idiopathic or in the setting of lung or heart diseases. Our team is composed of investigators in 4 different academic institutions in 3 different states, with enormous expertise in all aspects of this proposal.

RC1HL100849

2009-09-30

2012-08-31