Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

描述（由申请人提供）：以患者为导向的研究（POR）提供了直接影响患者护理和结果的机会。年轻的调查人员需要在正确进行POR方面接受培训。这项建议提供了受保护的时间，以指导年轻的受训人员设计和实施贫穷经验，以实现具体的研究目标。侵袭性真菌感染（IFIs）的发病率在过去三十年中急剧增加，接受实体器官和造血干细胞移植（HSCT）的患者患这些通常致命的感染的风险很高。缺乏敏感、快速的检测手段来帮助对国际金融机构进行早期诊断，是造成高死亡率的原因之一。开发一种可靠的ifi早期诊断方法，将有助于在更适合治疗的感染阶段进行治疗。此外，如果一种抗真菌方案可以安全地给予发生IFI的高风险患者，并且可以在不诱导产生耐药性的情况下预防感染，那么移植领域将大大受益。因此，本提案的具体研究目的是：1)评估预防高风险移植人群中ifi的新预防方案；2)确定易患ifi的遗传决定因素，从而区分哪些移植受者将从抗真菌预防中获益最多；3)评估用于高风险人群中ifi快速诊断的新实验室分析方法。这些目标将通过我或我的学员设计和实施的一系列临床研究来实现。预防：吸入两性霉素B脂质复合物（ABLC）的疗效将通过一项多中心随机试验在异体造血干细胞移植人群中确定。雾化ABLC可以提供对真菌疾病的保护，同时避免与全身给药相关的毒性。易感性的遗传决定因素：在小鼠模型中发现有助于侵袭性曲霉病（IA）易感性的基因将在移植受体中进行研究，以调查它们在人类对IA易感性中的作用。新的诊断方法：将确定肺移植和儿童造血干细胞移植受者的性能特征和连续监测葡聚糖测定的诊断价值。目前正在开发的用于诊断念珠菌的实时PCR检测将优化用于临床实验室，并将在移植人群中评估PCR检测的连续监测的临床效用。

DESCRIPTION (provided by applicant): Patient-oriented research (POR) offers the opportunity to directly impact patient care and outcomes. Young investigators need training in the proper conduct of POR. This proposal provides protected time for mentoring young trainees in the design and conduct of POR in order to address specific research aims. The incidence of invasive fungal infections (IFIs) has increased dramatically over the past thirty years, and patients undergoing solid organ and hematopoietic stem cell transplantation (HSCT) are at high risk for these often lethal infections. The lack of sensitive, rapid tests to aid in early diagnosis of IFIs contributes to the high mortality. Development of a reliable early diagnostic assay for IFIs would facilitate treatment at a stage of infection more amenable to therapy. Furthermore, if an antifungal regimen could be safely given to patients at high risk for developing IFI and could prevent infection without inducing the development of resistance, the field of transplantation would benefit greatly. Therefore, the specific research aims of this proposal are to 1) assess new prophylactic regimens for prevention of IFIs in high risk transplant populations, 2) identify genetic determinants that predispose to IFIs and thereby distinguish transplant recipients who would most benefit from antifungal prophylaxis, and 3) assess new laboratory assays for rapid diagnosis of IFIs in high risk populations. These aims will be met through a series of clinical investigations designed and conducted by me or my trainees. Prophylaxis: Efficacy of inhaled amphotericin B lipid complex (ABLC) will be determined in the allogeneic HSCT population through a multicenter, randomized trial. Aerosolized ABLC may provide protection against fungal disease while avoiding toxicity associated with systemic administration. Genetic Determinants of Susceptibility: Genes found to contribute to invasive aspergillosis (IA) susceptibility in a murine model will be studied in transplant recipients to investigate their role in human susceptibility to IA. Novel Diagnostics: Performance characteristics and the diagnostic value of serial monitoring with the glucan assay in lung transplant and pediatric HSCT recipients will be determined. A realtime PCR assay for diagnosis of candidemia currently under development will be optimized for use in the clinical laboratory and the clinical utility of serial monitoring with the PCR assay will be assessed in transplant populations.