The Platelet Transcriptome and Organ Failure After Injury: Discovering Molecular Biomarkers and Preventative Targets through Interrogating Novel RNA Modifications

血小板转录组和损伤后器官衰竭：通过研究新的 RNA 修饰发现分子生物标志物和预防靶点

• 批准号: 10711791
• 负责人: Lucy Kornblith
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711791
• 关键词: Acute; Address; Area; Award; Basic Science; Biological Models; Biological Process; Biology; Blood Platelets; Caring; Cause of Death; Cessation of life; Development; Disease; Early identification; Early treatment; Foundations; Functional disorder; Genetic Transcription; Health; Human Biology; Infrastructure; Injury; K-Series Research Career Programs; Knowledge; Measures; Megakaryocytes; Mentors; Methods; Mission; Modification; Morbidity - disease rate; National Institute of General Medical Sciences; Organ failure; Patients; Physiological; Physiology; Prevention; Public Health; RNA; Research; Research Personnel; Resolution; Sampling; Science; Scientist; Signal Transduction; Site-Directed Mutagenesis; Surgeon; Survivors; Testing; Therapeutic; Transgenic Organisms; Trauma; clinically relevant; disease diagnosis; high risk; improved; in vitro Model; in vivo Model; injured; injury burden; innovation; molecular marker; mortality; next generation sequencing; novel; organ growth; pharmacologic; platelet function; prevent; research clinical testing; ribosome profiling; severe injury; thromboinflammation; transcriptome; transcriptomics; translational study

Project Summary/Abstract As a trauma surgeon-scientist and early stage investigator in the 5th year of an NIGMS mentored career development award for the translational study of post-injury platelet function, I have developed expertise, infrastructure, and made significant contributions to demonstrating that early platelet dysfunction after injury is common, driven by changing physiology, and associated with later development of organ failure. This is important because injury remains a leading cause of death worldwide, but advances in initial care have shifted the burden of injury-related morbidity and mortality from early after injury to later, leaving two important challenges:1) identifying injured survivors at highest risk of developing initial and sustained organ failure leading to long-term morbidity and late mortality, and 2) discovering novel targets for early therapies to prevent development of organ failure after injury. Platelets contribute to organ failure through pathobiology in thromboinflammation. In similar diseases, platelet transcriptomics has improved mechanistic understandings and driven exploration of platelet-based therapeutics. Platelet megakaryocyte derived ribonucleic acids (RNAs) are stable in health, but modified by physiological signals in disease. Importantly, platelets are anucleate and lack RNA synthesis, thus providing the cleanest transcriptomic view of RNA modification in human biology. As such, my proposal seeks to re- imagine how we understand, measure, and intervene on early alterations in platelets after injury by focusing on the platelet transcriptome to explore prediction and prevention of organ failure among patients who initially survive their injuries, and to identify RNA modification targets that can be tested in model systems by addressing these knowledge gaps: 1) Identify the early platelet transcriptional landscape of severe injury and its relationship to development and resolution of organ failure in longitudinal patient studies; 2) Define the effect of platelet RNA modifications on platelet function in samples from patients with severe injury and in ex vivo modified healthy platelets; 3) Develop ex vivo and in vitro model systems to manipulate clinically relevant platelet RNA modifications as ultimate conduits to in vivo models and clinical testing. I will use feasible (next generation sequencing, ribosome footprint profiling), and novel (sub-population sequencing, ex vivo transgenic platelet model systems) methods to identify novel molecular biomarkers and preventative targets of development of organ failure after injury, and innovate our understanding of physiologically driven RNA modification through the ideal anucleate biology of platelets under the optimal acute physiologic changes of injury. This K to R award transition proposal is NIGMS mission-focused by using basic research to increase understanding of biological processes and lay the foundation for advances in disease diagnosis, treatment, and prevention within the area of ‘Injury’ (Pharmacological and Physiological Sciences Branch).

项目总结/摘要 作为一名创伤外科医生，科学家和早期研究员，在NIGMS指导职业生涯的第5年 发展奖的翻译研究损伤后血小板功能，我已经开发的专业知识， 基础设施，并作出了重大贡献，证明损伤后早期血小板功能障碍， 常见，由生理变化驱动，并与器官衰竭的后期发展相关。这是 这一点很重要，因为伤害仍然是全球死亡的主要原因，但初始护理的进步已经改变了 损伤相关的发病率和死亡率的负担从损伤后早期到后期，留下两个重要的 挑战：1）确定受伤的幸存者发展初期和持续器官衰竭的最高风险 导致长期发病率和晚期死亡率，以及2）发现早期治疗的新靶点，以预防 损伤后器官衰竭的发展。 血小板通过血栓炎症的病理生物学作用导致器官衰竭。在类似疾病中，血小板 转录组学提高了对机制的理解，并推动了对基于血小板的 治疗学血小板巨核细胞衍生的核糖核酸（RNA）在健康状态下是稳定的，但被修饰 疾病中的生理信号重要的是，血小板是无核的并且缺乏RNA合成，因此提供了 人类生物学中RNA修饰的最清晰的转录组学观点。因此，我的建议旨在重新- 想象一下，我们如何通过关注受伤后血小板的早期变化来理解、测量和干预 血小板转录组，以探讨预测和预防器官衰竭的患者中，最初 并确定可以在模型系统中测试的RNA修饰靶点， 解决这些知识差距：1）确定严重损伤的早期血小板转录景观， 在纵向患者研究中，其与器官衰竭的发展和解决的关系; 2）定义 血小板RNA修饰对严重损伤患者样本和体外实验中血小板功能的影响 体内修饰的健康血小板; 3）开发离体和体外模型系统，以操纵临床相关的 血小板RNA修饰作为体内模型和临床测试的最终管道。我将使用可行的（下一个 代测序，核糖体足迹分析）和新的（亚群测序，离体转基因 血小板模型系统）的方法来鉴定新的分子生物标志物和预防性靶点， 损伤后器官衰竭的发展，并创新我们对生理驱动RNA的理解 在最佳急性生理变化下，通过血小板的理想无核生物学进行修饰， 损伤这项K to R奖项过渡提案是NIGMS以任务为中心，利用基础研究来增加 了解生物过程，并为疾病诊断，治疗， 和预防领域内的“损伤”（药理学和生理科学分支）。