Zipcode based nano-imaging of hypertensive pulmonary arteries

描述(申请人提供)：本申请涉及挑战领域06“使能技术和预防”和具体挑战主题06-HL-104“使能技术涉及开发用于肺部医学的纳米工具，特别是旨在更安全和更有效地给药延长生命的药物，如治疗肺动脉高压的前列环素”。重度肺动脉高压(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的高死亡率相关。该病以复杂的肺血管病变为特征，包括内皮细胞增殖所致的丛状病变。目前的治疗方法，包括前列环素和磷酸二酯酶抑制剂，可以延长生存期，但并不能导致疾病的消退或治愈。此外，半个多世纪前已经开始实施的有创性血流动力学肺动脉压评估是诊断SPH的晚期。SPH最重要的挑战是克服早期诊断工具的缺乏，缺乏监测肺血管对潜在全身治疗的反应的非侵入性方法，以及无法直接将疾病修饰药物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，我们建议发现多肽/受体对，这将允许开发用于诊断SPH的肺血管成像的纳米设备。我们假设肺血管内皮细胞具有独特的分子标记，该标记提供了由噬菌体显示屏上的结合多肽定义的特定的分子邮政编码。这些多肽可用于利用带有噬菌体纳米金或纳米金多肽装置的分子纳米平台进行细胞特异性诊断成像。特定目标1将定义与SPH相关的内皮细胞配体/受体对。特异靶向2将形成靶向靶向噬菌体或在靶标1中发现的多肽的SPH特异性纳米金平台，用于诊断SPH的肺血管病变。该提案依赖于一种综合和多学科的方法，使用SPH患者的正常和患病的人类肺组织、相关的细胞培养、动物模型和针对肺血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，他们拥有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设备组装(Pasquini/Arap)、纳米设备组装和化学(Boyes)以及活体光学、计算机断层扫描和磁共振成像(Serkova)等方面的专业知识。我们的研究可能会提供专业知识，可以扩展到针对肺血管病变的疾病特异性给药的开发，针对不同形式的肺动脉高压的定制成像，以及发现生物标记物的潜力。 公共卫生相关性：肺动脉高压是一种严重的疾病，由将血液从心脏右侧输送到肺部的血管压力增加引起。肺动脉高压可能是一种孤立的情况，也称为特发性肺动脉高压，也可能是自身免疫性疾病或其他形式的肺部疾病的并发症。一旦出现，它就会带来不良的预后。肺动脉高压领域的主要挑战是在不必将探头放入患者心脏的情况下诊断疾病的能力，理想的情况是使用受影响肺血管的成像(即X射线)。如果完成，基于肺血管成像的诊断可以用于监测接受药物治疗的患者。我们的方法使用一种名为噬菌体的病毒来寻找独特的“压缩”地址，这种地址可以让分子找到肺动脉高压中的病变肺血管。我们计划制造纳米设备(Nano指的是这些设备非常小，只有人类头发厚度的百分之一)。这些设备随后将传播到受影响的肺血管，并允许我们使用想象工具来可视化受影响的血管。我们的研究依赖于发现这些邮政编码的第一阶段，然后制造出这些设备，在培养皿中生长的人类细胞和患有与人类相似的疾病的大鼠身上进行测试。我们还可以使用这些设备只将药物输送到患病细胞，并建造可以诊断特定形式的肺高压的设备，例如特发性或肺或心脏病的背景。我们的团队由来自3个不同州的4个不同学术机构的研究人员组成，在这项提案的所有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.