Prognostic biomarkers for respiratory failure post hematopoietic cell transplantation

造血细胞移植后呼吸衰竭的预后生物标志物

基本信息

批准号：
10055267
负责人：
Courtney Rowan
金额：
$ 17.93万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10055267
关键词：
Acute respiratory failure Adult Adult Respiratory Distress Syndrome Allogenic Appearance Award Biological Biological Markers Blood Tests Bone Marrow Transplantation Caring Child Clinical Clinical Research Clinical Trials Complication Critical Illness Data Development Development Plans Diagnostic Disease Distress Early Intervention Early identification Etiology Event Foundations Funding Future Genetic Diseases Goals Hematological Disease Idiopathic pneumonia syndrome Incidence Indiana Interleukin-6 Intubation Kinetics Knowledge Lead Life Lung Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Measures Medical Mentors Mentorship Metabolic Diseases Methods Modeling Monitor Multicenter Studies Non-Malignant Pathway interactions Patients Phase Plasma Population Positioning Attribute Prevention Prognostic Marker Prospective Studies Proteins Proteomics Research Respiratory Failure Respiratory Signs and Symptoms Risk Sampling Savings Statistical Methods Supportive care TNFRSF1A gene Testing Time Training Translating Translational Research Transplant Recipients United States National Institutes of Health Universities Validation Work base biomarker development biomarker panel candidate marker career career development clinical biomarkers clinical practice cohort design experience hematopoietic cell transplantation high risk implementation science improved innovation interest medical schools mortality novel novel strategies novel therapeutics outcome forecast pediatric patients personalized medicine power analysis predictive modeling preemptive intervention prevent prognostic prognostic assays prognostic value prospective receptor research study skills tandem mass spectrometry targeted treatment

项目摘要

PROJECT SUMMARY While hematopoietic cell transplantation (HCT) is a life-saving therapy for previously fatal malignant and nonmalignant conditions, pulmonary complications such as respiratory failure (RF) remain a barrier. Currently there is no objective way to determine risk of developing RF, thereby limiting opportunities for early intervention and prevention. We have identified 3 biomarkers, including stimulation 2 (ST2, the IL-33 receptor), interleukin 6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), which hold extreme promise for prognosis of future occurrence of RF when measured as early as day 7 post HCT, well before typical onset of clinical respiratory symptoms. Furthermore, we have conducted the two phases of proteomic discovery using mass spectrometry and have identified 11 additional candidate biomarkers, in addition to ST2, to validate in an independent cohort. Therefore, we hypothesize that prognostic biomarkers can serve as an early warning for the HCT recipient at increased risk for RF. In Aim 1, we propose to investigate the effect of dynamic changes of validated biomarkers at days 0, 7, 14, and 21 post-HCT on prognosis for RF. We will then, in Aim 2, validate additional diagnostic and prognostic candidate biomarkers for RF discovered through our proteomics pipeline. Finally, in Aim 3, we will conduct a prospective real-time multicenter study to determine RF prognostic biomarkers thresholds for enabling a biomarker-based preemptive trial In addition to elucidating biologic etiologies of RF that could lead to improved targeted therapies, this work will lay the foundation for a biomarker-based preemptive clinical trial aimed to reduce RF and RF-related mortality post-HCT. During the award period, I will conduct research at Indiana University School of Medicine under the primary mentorship of Dr. Sophie Paczesny and the remainder of the co-mentors, advisors and collaborators outlined in the career development plan. I will focus on gaining critical skills in translational research needed to successfully compete for NIH-funding and launch an independent research career. Specifically, I will develop a comprehensive knowledge of clinical biomarker development, proteomic discovery using mass spectrometry, advanced statistical methods to approach biomarker research including prognostic modeling, and skills in implementation science to be able to translate these discoveries into clinical practice. With expertise in acute respiratory failure post-HCT, experience leading multicenter collaborative clinical research studies in this population, and a strong team of mentors and advisors, I am uniquely positioned to successfully complete the proposed study and transition to an independent research career.

项目概要虽然造血细胞移植 (HCT) 是一种挽救生命的疗法，用于治疗先前致命的恶性和对于非恶性疾病，呼吸衰竭（RF）等肺部并发症仍然是一个障碍。现在没有客观的方法来确定发生 RF 的风险，从而限制了早期干预的机会和预防。我们已经鉴定出 3 个生物标志物，包括刺激 2（ST2，IL-33 受体）、白细胞介素 6 (IL-6) 和肿瘤坏死因子受体 1 (TNFR1)，它们对未来的预后具有极大的希望最早在 HCT 后第 7 天测量时出现 RF，远早于临床呼吸典型发作症状。此外，我们利用质谱法进行了蛋白质组学发现的两个阶段除 ST2 外，还确定了另外 11 种候选生物标志物，以在独立队列中进行验证。因此，我们假设预后生物标志物可以作为 HCT 接受者的早期预警。射频风险增加。在目标 1 中，我们建议研究已验证生物标志物动态变化的影响 HCT 后第 0、7、14 和 21 天的 RF 预后。然后，我们将在目标 2 中验证额外的诊断和通过我们的蛋白质组学管道发现的 RF 预后候选生物标志物。最后，在目标 3 中，我们将进行前瞻性实时多中心研究，以确定射频预后生物标志物阈值，以实现基于生物标志物的先发性试验除了阐明 RF 的生物学病因之外，还可能导致改善靶向治疗，这项工作将为基于生物标志物的先发性临床试验奠定基础，旨在降低 HCT 后 RF 和 RF 相关死亡率。获奖期间，我将在印第安纳大学医学院进行研究 Sophie Paczesny 博士和其他共同导师、顾问和合作者的主要指导职业发展计划中列出。我将专注于获得转化研究所需的关键技能成功竞争 NIH 资助并开启独立研究生涯。具体来说，我将开发一个临床生物标志物开发、利用质谱发现蛋白质组的综合知识，进行生物标志物研究的先进统计方法，包括预后建模和技能实施科学能够将这些发现转化为临床实践。凭借急症方面的专业知识 HCT 后呼吸衰竭，在这方面拥有领先的多中心协作临床研究经验人口以及强大的导师和顾问团队，我具有独特的优势来成功完成提议学习并过渡到独立研究职业。