Novel Clinical Diagnostic Targets For Detection of Invasive Mold Aspergillosis

描述（由申请人提供）：侵袭性曲霉病（Invasive aspergilllosis， IA）是导致免疫功能低下患者死亡的一个重要原因，尤其是那些患有癌症、糖尿病、艾滋病或接受实体器官或造血干细胞移植的患者（Ascioglu et al., 2002; Cornely, 2008）。在过去的几十年里，由于具有潜在危险因素的患者数量持续增加，IA的发生率增加。值得注意的是，曲霉菌约占真菌感染总数的15%，在高危人群中死亡率超过80-90% （Walsh等人，2008）。真菌负担相对较低的早期治疗可能对IMI的预后至关重要。由于临床症状不明确且缺乏可靠的诊断工具，因此对IA的立即和结论性检测仍然是一个难题。因此，新的诊断方法代表了一个未满足的和紧迫的医疗保健需求。真菌生物标志物有可能有助于IA的诊断和治疗监测，以及提供抗真菌治疗的靶点到感染部位。我们已经发表了一些研究，描述了选择性相互作用配体的生物筛选和快速分析（BRASIL）方法及其在鉴定与曲霉菌丝和分生孢子结合的肽方面的应用（Giordano等人，2001；Lionakis等人，2005）。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度作为分子网络，将基于噬菌体展示的靶向技术扩展到纳米技术应用中（Souza等人，2006a）。我们生成了稳定和生物活性的直接组装的金噬菌体网络，具有独特和可调的化学和物理性质。这种调节能力与噬菌体的编程靶向相结合，可以将多种功能集成到单个纳米组装中。我们设想靶向的au噬菌体网络或相应标记的靶向肽将成为IA诊断和治疗监测的可靠图像平台。我们的建议是围绕使用靶向噬菌体Au纳米粒子分子网络或标记的靶向肽来诊断iA。我们的长期目标是为IA和其他侵袭性真菌感染开发一种高灵敏度的成像诊断方法。为此，将开发IA诊断的成像平台，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。

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.