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

• 批准号: 10688031
• 负责人: Courtney Rowan
• 金额: $ 18.04万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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/10688031
• 关键词: Acute Respiratory Distress Syndrome; Acute respiratory failure; Adult; Allogenic; Appearance; Award; Biological; Biological Assay; 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; Hospitalization; Idiopathic pneumonia syndrome; Incidence; Indiana; Interleukin-6; Intubation; Kinetics; Knowledge; 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; Prognosis; Prognostic Marker; Prospective Studies; Proteins; Proteomics; Research; Respiratory Failure; Respiratory Signs and Symptoms; Risk; Sampling; Statistical Methods; Supportive care; TNFRSF1A gene; Testing; Time; Training; Translating; Translational Research; Transplant Recipients; United States National Institutes of Health; Universities; Validation; Work; biomarker development; biomarker panel; biomarker validation; 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; pediatric patients; personalized medicine; power analysis; preemptive intervention; prevent; prognostic; prognostic model; prognostic value; prospective; receptor; research study; skills; tandem mass spectrometry; targeted treatment

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.

项目摘要 而造血细胞移植（HCT）是一种挽救生命的疗法，用于以前致命的恶性肿瘤和 非恶性状况，肺部并发症（例如呼吸衰竭（RF））仍然是障碍。现在 没有客观的方法来确定开发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），白介素6 （IL-6）和肿瘤坏死因子受体1（TNFR1），这对未来的预后有极大的希望 在HCT后第7天测量时，RF发生在典型的临床呼吸发作之前 症状。此外，我们使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11种其他候选生物标志物，以在独立队列中验证。 因此，我们假设预后生物标志物可以作为HCT接受者的预警 RF的风险增加。在AIM 1中，我们建议研究已验证的生物标志物的动态变化的影响 在第0、7、14和21天HCT时，RF的预后。然后，我们将在AIM 2中验证其他诊断和 通过我们的蛋白质组学管道发现的RF的预后候选生物标志物。最后，在AIM 3中，我们将 进行一项前瞻性实时多中心研究，以确定RF预后生物标志物阈值以实现 除了阐明RF的生物学病因外，基于生物标志物的预先试验可能会改善 有针对性的疗法，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 HCT后降低RF和RF相关的死亡率。 在奖励期间，我将在印第安纳大学医学院进行研究 索菲·帕切斯尼（Sophie Paczesny）博士的主要指导以及剩下的联席会员，顾问和合作者 在职业发展计划中概述了。我将专注于在需要的转化研究中获得关键技能 成功竞争NIH资助并启动独立的研究职业。具体来说，我会开发一个 全面了解临床生物标志物发展，使用质谱法发现蛋白质组学的知识， 采用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。具有急性专业知识 HCT后呼吸衰竭，经验领先的多中心协作临床研究研究 人口，以及由指导者和顾问组成的强大团队，我独特地可以成功完成 拟议的研究和过渡到独立研究职业。

项目成果

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

• DOI: 10.1097/mat.0000000000001336
• 发表时间: 2021-08-01
• 期刊: ASAIO journal (American Society for Artificial Internal Organs : 1992)
• 作者: Bridges BC;Kilbaugh TJ;Barbaro RP;Bembea MM;Chima RS;Potera RM;Rosner EA;Sandhu HS;Slaven JE;Tarquinio KM;Cheifetz IM;Rowan CM;Friedman ML;Pediatric ECMO (Pediecmo) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Extracorporeal Life Support Organization (ELSO)
• 通讯作者: Pediatric ECMO (Pediecmo) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Extracorporeal Life Support Organization (ELSO)

The association of postoperative dexmedetomidine with pain, opiate utilization, and hospital length of stay in children post-Chiari malformation decompression.

• DOI: 10.3171/2021.10.peds21291
• 发表时间: 2022-03-01
• 期刊: JOURNAL OF NEUROSURGERY-PEDIATRICS
• 影响因子: 1.9
• 作者: Cater, Daniel T.;Rogerson, Colin M.;Hobson, Michael J.;Ackerman, Laurie L.;Rowan, Courtney M.
• 通讯作者: Rowan, Courtney M.

Vascular thrombosis after pediatric liver transplantation: Is prevention achievable?

小儿肝移植后血管血栓：可以预防吗？

• DOI: 10.1016/j.liver.2023.100185
• 发表时间: 2023
• 期刊: Journal of liver transplantation
• 作者: Martinez,Mercedes;Kang,Elise;Beltramo,Fernando;Nares,Michael;Jeyapalan,Asumthia;Alcamo,Alicia;Monde,Alexandra;Ridall,Leslie;Kamath,Sameer;Betters,Kristina;Rowan,Courtney;Mangus,RichardShane;Kaushik,Shubhi;Zinter,Matt;Resch,Jo
• 通讯作者: Resch,Jo

Immunocompromised-Associated Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

免疫功能低下相关的小儿急性呼吸窘迫综合征：2016/2017 年小儿急性呼吸窘迫综合征发病率和流行病学前瞻性队列研究的经验。

• DOI: 10.1097/pcc.0000000000003421
• 发表时间: 2024
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Gertz,ShiraJ;Bhalla,Anoopindar;Chima,RanjitS;Emeriaud,Guillaume;Fitzgerald,JulieC;Hsing,DeyinD;Jeyapalan,AsumthiaS;Pike,Francis;Sallee,ColinJ;Thomas,NealJ;Yehya,Nadir;Rowan,CourtneyM;PediatricAcuteRespiratoryDistressSyn
• 通讯作者: PediatricAcuteRespiratoryDistressSyn

Extracorporeal membrane oxygenation in children receiving haematopoietic cell transplantation and immune effector cell therapy: an international and multidisciplinary consensus statement.

• DOI: 10.1016/s2352-4642(21)00336-9
• 发表时间: 2022-03
• 期刊: LANCET CHILD & ADOLESCENT HEALTH
• 影响因子: 36.4
• 作者: Di Nardo, Matteo;Ahmad, Ali H.;Merli, Pietro;Zinter, Matthew S.;Lehman, Leslie E.;Rowan, Courtney M.;Steiner, Marie E.;Hingorani, Sangeeta;Angelo, Joseph R.;Abdel-Azim, Hisham;Khazal, Sajad J.;Shoberu, Basirat;McArthur, Jennifer;Bajwa, Rajinder;Ghafoor, Saad;Shah, Samir H.;Sandhu, Hitesh;Moody, Karen;Brown, Brandon D.;Mireles, Maria E.;Steppan, Diana;Olson, Taylor;Raman, Lakshmi;Bridges, Brian;Duncan, Christine N.;Choi, Sung Won;Swinford, Rita;Paden, Matt;Fortenberry, James D.;Peek, Giles;Tissieres, Pierre;De Luca, Daniele;Locatelli, Franco;Corbacioglu, Selim;Kneyber, Martin;Franceschini, Alessio;Nadel, Simon;Kumpf, Matthias;Loreti, Alessandra;Wosten-Van Asperen, Roelie;Gawronski, Orsola;Brierley, Joe;MacLaren, Graeme;Mahadeo, Kris M.
• 通讯作者: Mahadeo, Kris M.