Novel Clinical Diagnostic Targets For Detection of Invasive Mold Aspergillosis

描述（由申请人提供）：侵袭性曲霉病（IA）是免疫功能低下患者死亡的严重原因，特别是那些患有癌症、糖尿病和HIV/AIDS或经历实体器官或造血干细胞移植的患者（Ascioglu等人，2002; Cornely，2008）。在过去的几十年里，IA的发生率升高，因为具有潜在风险因素的患者数量持续增加。值得注意的是，曲霉属占总真菌感染的约15%，在高风险组中死亡率超过80-90%（沃尔什等人，2008年）。真菌负荷相对较低时的早期治疗对IMI的结局至关重要。IA的即时和结论性检测仍然是一个难题，因为临床症状不明确，可靠的诊断工具不足。因此，新的诊断方法代表了一个未满足和迫切的医疗保健需求。真菌生物标志物有可能有助于IA的诊断和治疗监测，并为感染部位的抗真菌治疗提供靶点。我们已经发表了描述生物淘选和选择性相互作用配体的快速分析（BRASIL）方法及其在鉴定与曲霉菌菌丝和分生孢子结合的肽中的效用的研究（Giordano等人，2001; Lionakis等人，2005年）。最近，我们通过将金（Au）纳米颗粒直接组装到噬菌体上，利用噬菌体颗粒的纳米尺寸作为分子网络，将基于噬菌体展示的靶向扩展到纳米技术应用（Souza等人，2006年a）。我们产生了稳定的和生物活性的直接组装的Au-噬菌体网络的网络，伴随着独特的和可调的化学和物理性质。这种调谐能力与噬菌体的程序化靶向相结合，提供了将多个功能整合到单个纳米组装体中。我们设想，无论是有针对性的金噬菌体网络或标记相应的靶向肽将成为一个可靠的图像平台，IA的诊断和治疗监测。我们的建议是围绕使用靶向噬菌体Au纳米颗粒分子网络或标记的靶向肽来诊断iA。我们的长期目标是开发一种高灵敏度的影像学诊断IA和其他侵袭性真菌感染的方法。为此，将开发一个诊断IA的成像平台，在侵袭性曲霉病的动物模型中验证该平台，并列举其药代动力学特性和毒性，以指导临床前研究。 公共卫生相关性：侵袭性曲霉菌病是免疫抑制白血病患者和移植受者发病和死亡的常见原因。早期诊断对于改善曲霉病的不良预后至关重要。在这里，我们建议使用噬菌体作为靶向部分的金（Au）纳米粒子为基础的真菌感染诊断成像。

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is a serious cause of mortality in immunocompromised patients, particularly those suffering from cancer, diabetes and HIV/AIDS or undergoing solid-organ or hematopoietic stem cell transplant (Ascioglu et al., 2002; Cornely, 2008). The occurrence of IA heightened over the past couple of decades because the number of patients with underlying risk factors continues to increase. Noteworthy, Aspergillus sp. account for approximately 15% of total fungal infections with a mortality that exceeds 80-90% in high risk groups (Walsh et al., 2008). Early treatment when the fungal burden is relatively low could be critical for the outcome of IMI. Immediate and conclusive detection of IA remains a conundrum since clinical symptoms are ambiguous and insufficient reliable diagnostic tools are available. Therefore, new diagnostic methods represent an unmet and pressing healthcare need. Fungal biomarkers have the potential to contribute to IA diagnosis and treatment monitoring as well as provide targets for antifungal therapy delivery to the site of infection. We have already published studies describing the Biopanning and Rapid Analysis of Selective Interacting Ligands (BRASIL) method and its utility in identification of peptides binding to Aspergillus hyphae and conidia (Giordano et al., 2001; Lionakis et al., 2005). More recently, we have expanded phage display- based targeting to nanotechnology applications through the direct-assembly of gold (Au) nanoparticles onto phage, exploiting the nanodimensions of the phage particle as a molecular network (Souza et al., 2006a). We generated stable and biologically active networks of direct-assembled Au-phage networks with concomitant unique and tunable chemical and physical properties. This tuning capability combined with the programmed targeting of the phage affords the integration of multiple functionalities into a single nanoassembly. We envision that either targeted Au-phage networks or labeled corresponding targeted peptides will become a reliable image platform for IA diagnosis and treatment monitoring. Our proposal is framed around the use of targeting phage Au nanoparticle molecular networks or labeled targeted peptides to diagnose iA. Our long-term goal is to develop a highly sensitive imaging diagnostic methodology for IA and other invasive fungal infections. To that end, will develop an imaging platform for diagnosis of IA, validate this platform in an animal model of invasive aspergillosis and enumerate its pharmacokinetical properties and toxicity to guide pre-clinical studies. PUBLIC HEALTH RELEVANCE: Invasive aspergillosis is a common cause of morbidity and mortality in immunosuppressed patients with leukemia and transplant recipients. Early diagnosis is of critical importance in improving the poor outcome of aspergillosis. Here we propose to use phage as targeting moieties for Gold (Au) nanoparticles based imaging for fungal infection diagnosis.