Prognostic biomarkers for respiratory failure post hematopoietic cell transplantation

项目总结 而造血细胞移植(HCT)是一种挽救生命的疗法，适用于先前致命的恶性肿瘤和 在非恶性情况下，呼吸衰竭(RF)等肺部并发症仍然是一个障碍。目前 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。我们已经确定了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)，这对未来的预后有着极大的希望 早在HCT后第7天，在典型的临床呼吸发作之前就测量到RF的发生 症状。此外，我们还利用质谱仪进行了蛋白质组发现的两个阶段。 除了ST2，还确定了另外11个候选生物标记物，以便在独立的队列中进行验证。 因此，我们假设预后生物标记物可以作为早期预警的红细胞移植受者。 增加了射频的风险。在目标1中，我们建议调查经过验证的生物标志物的动态变化的影响 HCT后第0、7、14、21天对RF预后的影响。然后，我们将在目标2中验证其他诊断和 通过我们的蛋白质组学流水线发现RF的预后候选生物标记物。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RF预后生物标志物阈值 一项基于生物标记物的预防性试验，除了阐明RF的生物病因外，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制人临床试验奠定基础，旨在 减少HCT后射频和射频相关死亡率。 在获奖期间，我将在印第安纳大学医学院进行研究， 索菲·帕切斯尼博士和其他共同导师、顾问和合作者的主要导师 在职业发展计划中概述。我将专注于获得翻译研究中所需的关键技能 成功争取美国国立卫生研究院资助，开启独立研究事业。具体地说，我将制定一个 全面了解临床生物标记物的开发，利用质谱学发现蛋白质组， 先进的统计方法来处理生物标记物研究，包括预后建模，以及 实现科学能够将这些发现转化为临床实践。在急诊方面具有专业知识 HCT后呼吸衰竭，在这方面领先的多中心协作临床研究 以及强大的导师和顾问团队，我处于独特的地位，能够成功地完成 建议学习并过渡到独立的研究生涯。

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.