Zipcode based nano-imaging of hypertensive pulmonary arteries

描述（由申请人提供）：本申请涉及“使能技术和预防”的挑战领域06和具体的挑战主题06- hl -104“涉及肺医学纳米工具开发的使能技术，特别是针对更安全、更有效地给药延长生命的药物，如用于肺动脉高压的前列环素”。严重肺动脉高压（SPH）是一种不可逆的恶性肺动脉压升高，通常与右侧心力衰竭引起的高死亡率相关。本病以复杂的肺血管病变为特征，包括内皮细胞增生引起的网状病变。目前的治疗方法，包括前列环素和磷酸二酯酶抑制剂延长生存期，但不能导致疾病的消退或治愈。此外，SPH是在晚期通过有创性肺动脉压血流动力学评估诊断出来的，这种方法在半个多世纪前就已经实施了。SPH最重要的挑战是克服缺乏早期诊断工具，缺乏无创方法来监测肺血管对潜在全身治疗的反应，以及无法将疾病改善药物直接输送到相关的肺血管病变。鉴于高血压肺血管病变中内皮细胞的独特表型特征，我们建议发现肽/受体对，这将允许开发用于SPH肺血管成像诊断的纳米设备。我们假设肺血管内皮细胞含有独特的分子标记，提供由结合肽的噬菌体显示屏幕定义的特定分子“zip”代码。这些肽可用于细胞特异性诊断成像，使用带有噬菌体纳米金或纳米金肽装置的分子纳米平台。特异性目标1将定义与SPH相关的内皮细胞配体/受体对。Specific Aim 2将构建针对Aim 1中发现的噬菌体或肽的SPH特异性纳米金平台，用于SPH肺血管病变的诊断成像。该提案依赖于综合和多学科的方法，使用SPH患者的正常和患病人肺组织，相关细胞培养，动物模型和针对肺脉管系统的最先进的噬菌体展示方法。为了实现这些目标，我们组建了一个跨学科的团队，具有SPH病理生物学和相关模型系统（Tuder和Erzurum），噬菌体展示方法和金噬菌体纳米器件组装（Pasqualini/Arap），纳米器件组装和化学（Boyes）以及体内光学，计算机断层扫描和磁共振成像（Serkova）的专业知识。我们的研究可能提供专业知识，可以扩展到针对肺血管病变的药物的疾病特异性递送的发展，针对不同形式的肺动脉高压的定制成像，以及潜在的生物标志物发现。

DESCRIPTION (provided by applicant): 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.