Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

职业生涯中期研究员奖：预防和诊断真菌病

• 批准号: 8072051
• 负责人: BARBARA D ALEXANDER
• 金额: $ 12.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072051
• 关键词: Address; Allogenic; Amphotericin B-Lipid Complex; Antifungal Agents; Aspergillosis; Award; Biological Assay; Breathing; Characteristics; Childhood; Clinical; Clinical Research; Clinical Trials; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Genetic Determinism; Glucans; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Incidence; Infection; Infection prevention; Laboratories; Lung; Mentors; Modeling; Monitor; Multicenter Trials; Mus; Mycoses; Organ; Outcome; Patient Care; Patients; Performance; Population; Predisposition; Prevention; Prophylactic treatment; Regimen; Research; Research Institute; Research Personnel; Resistance development; Role; Series; Site; Solid; Staging; Stem cell transplant; Susceptibility Gene; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplantation; aerosolized; candidemia; career; design; high risk; innovation; meetings; mortality; novel diagnostics; patient oriented research; prevent; prophylactic; randomized trial; rapid diagnosis

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.

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。年轻的研究者需要接受正确进行 POR 的培训。该提案为指导年轻学员设计和实施 POR 提供了受保护的时间，以实现特定的研究目标。过去三十年来，侵袭性真菌感染 (IFI) 的发病率急剧增加，接受实体器官和造血干细胞移植 (HSCT) 的患者面临着这些往往致命的感染的高风险。缺乏敏感、快速的检测来帮助早期诊断 IFI，导致了高死亡率。开发一种可靠的 IFI 早期诊断检测方法将有助于在更适合治疗的感染阶段进行治疗。此外，如果抗真菌疗法能够安全地给予发生IFI的高风险患者，并且能够预防感染而不诱导耐药性的产生，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）评估用于预防高危移植人群中 IFI 的新预防方案，2）确定易患 IFI 的遗传决定因素，从而区分最能从抗真菌预防中受益的移植受者，以及 3）评估用于快速诊断高危人群中 IFI 的新实验室检测方法。这些目标将通过我或我的学员设计和进行的一系列临床研究来实现。预防：吸入性两性霉素 B 脂质复合物 (ABLC) 的疗效将通过多中心、随机试验在同种异体 HSCT 人群中确定。雾化 ABLC 可提供针对真菌病的保护，同时避免与全身给药相关的毒性。易感性的遗传决定因素：在小鼠模型中发现的导致侵袭性曲霉病 (IA) 易感性的基因将在移植受者中进行研究，以研究它们在人类对 IA 易感性中的作用。新型诊断：将确定肺移植和儿科 HSCT 受者中葡聚糖测定连续监测的性能特征和诊断价值。目前正在开发的用于诊断念珠菌血症的实时 PCR 检测将被优化以用于临床实验室，并且将评估 PCR 检测连续监测的临床效用在移植群体中的应用。

项目成果

Factors associated with mortality in transplant patients with invasive aspergillosis.

• DOI: 10.1086/652768
• 发表时间: 2010-06-15
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Baddley JW;Andes DR;Marr KA;Kontoyiannis DP;Alexander BD;Kauffman CA;Oster RA;Anaissie EJ;Walsh TJ;Schuster MG;Wingard JR;Patterson TF;Ito JI;Williams OD;Chiller T;Pappas PG
• 通讯作者: Pappas PG

Fungal diagnostics in pneumonia.

• DOI: 10.1055/s-0031-1295714
• 发表时间: 2011-12
• 期刊: Seminars in respiratory and critical care medicine
• 影响因子: 3.2
• 作者: Lease ED;Alexander BD
• 通讯作者: Alexander BD