Zipcode based nano-imaging of hypertensive pulmonary arteries

描述（由申请人提供）：本申请涉及挑战领域06“使能技术和预防”和特定挑战主题06-HL-104“涉及肺部医学纳米工具开发的使能技术，特别是旨在更安全和更有效地给予延长生命的药物，如前列环素治疗肺动脉高压”。重度肺动脉高压（SPH）是一种不可逆的恶性肺动脉压力升高，通常与右侧心力衰竭导致的高死亡率相关。该疾病的特征在于复杂的肺血管病变，包括由于内皮细胞增殖引起的丛状病变。目前的治疗，包括前列环素和磷酸二酯酶抑制剂延长生存期，但不会导致疾病的消退或治愈。此外，SPH是在晚期通过肺动脉压力的侵入性血流动力学评估来诊断的，该评估已经在超过半个世纪前实施。SPH中最重要的挑战是克服缺乏早期诊断工具，缺乏非侵入性方法来监测肺血管对潜在全身治疗的反应，以及无法将疾病修饰药物直接递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诊断肺血管成像的纳米器件。我们假设肺血管内皮细胞具有独特的分子标记，这些标记提供了由结合肽的噬菌体展示屏幕定义的特定分子“邮政编码”。这些肽可用于使用具有噬菌体纳米金或纳米金肽装置的分子纳米平台的细胞特异性诊断成像。具体目标1将定义与SPH相关的内皮细胞配体/受体对。具体目标2将制定SPH特异性纳米金平台的目标1中发现的靶向肽或肽的诊断成像的肺血管病变的SPH。该提案依赖于一种全面且多学科的方法，使用SPH患者的正常和患病人肺组织、相关细胞培养物、动物建模以及针对肺血管系统的最新噬菌体展示方法。为了实现这些目标，我们组建了一个跨学科团队，拥有SPH病理生物学和相关模型系统（Tuder和Erzurum），噬菌体展示方法学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。我们的研究可以提供专业知识，可以扩展到疾病特异性药物输送机制，靶向肺血管病变，定制成像不同形式的肺动脉高压，和生物标志物发现的潜力的发展。 公共卫生相关性：肺动脉高压是一种严重的疾病，由从心脏右侧向肺部输送血液的血管中的压力增加引起。肺动脉高压可以作为一种孤立的疾病发生，也称为特发性肺动脉高压，或作为自身免疫性疾病或其他形式的肺部疾病的并发症。当它出现时，它会带来不良的预后。肺动脉高压领域的主要挑战是诊断疾病的能力，而不必将探头放入患者的心脏，理想情况下使用受影响的肺血管的成像（即X射线）。如果完成，基于肺血管成像的诊断可用于监测接受药物治疗的患者。我们的方法使用一种称为噬菌体的病毒来寻找独特的“zip”地址，可以让一个分子找到肺动脉高压中患病的肺血管。我们计划制造纳米器件（纳米指的是这些器件非常小，在人类头发厚度的百分之一范围内）。然后，这些设备将移动到受影响的肺血管，并允许我们使用成像工具来可视化病变血管。我们的研究依赖于发现这些邮政编码的第一阶段，然后构建这些设备，在培养皿中生长的人类细胞和患有与人类相似疾病的大鼠中进行测试。我们还可以使用这些设备将药物仅输送到患病细胞，并构建可以诊断特定形式的肺动脉高压的设备，例如特发性或肺部或心脏疾病。我们的团队由来自3个不同州的4个不同学术机构的调查人员组成，他们在该提案的各个方面都拥有丰富的专业知识。

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.