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; 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).

项目摘要/摘要 作为外科医生科学家和早期调查员，在纽格斯指导职业的第五年 伤害后血小板功能的转化研究奖，我已经开发了专业知识， 基础设施，并为证明受伤后的早期血小板功能障碍做出了重大贡献 常见，由生理变化驱动，并与后来的器官衰竭有关。这是 重要的是因为受伤仍然是全球死亡的主要原因，但是初始护理的进步已经改变 从受伤后早期到后来，与伤害相关的发病率和死亡率燃烧，留下了两个重要的 挑战：1）确定受伤的生存，处于发展最初和持续器官衰竭的风险最高 导致长期发病率和晚期死亡率，以及2）发现早期疗法的新目标，以防止 受伤后器官衰竭的发展。 血小板在血栓炎症中通过病理生物学导致器官衰竭。在类似疾病中，血小板 转录组学改善了机械理解和对基于血小板的驱动探索 疗法。血小板巨核细胞衍生的核糖核酸（RNA）在健康状态下稳定，但被修饰 疾病的生理信号。重要的是，血小板是Annucleate，缺乏RNA合成，因此提供 人类生物学中RNA修饰的最清洁转录组。因此，我的建议试图重新 想象我们如何通过专注于受伤后血小板的早期变化，通过关注 血小板转录组，以探索最初的患者预测和预防器官衰竭 生存他们的受伤，并确定可以通过模型系统测试的RNA修饰靶标 解决这些知识差距：1）确定重度伤害的早期血小板转录景观和 它与纵向患者研究中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和EX患者的样品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 血小板RNA修饰是体内模型和临床测试的最终导管。我将使用可行的（接下来 生成测序，核糖体足迹分析）和新颖（亚种群测序，离体转基因 血小板模型系统）方法是鉴定新的分子生物标志物和预防靶标的方法 受伤后器官衰竭的发展和创新我们对身体驱动的RNA的理解 在理想的急性生理变化下，通过理想的血小板的理想ANCLETE生物学修饰 受伤。通过使用基础研究来增加，这项K奖奖奖授予过渡提案是针对攻击任务的。 了解生物过程并为疾病诊断，治疗的进步奠定基础 和“损伤”区域内的预防（药理和生理科学分支）。