Novel Activities of Platelets in Acute Lung Injury

血小板在急性肺损伤中的新活性

• 批准号: 7559570
• 负责人: Andrew S Weyrich
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559570
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Adult Respiratory Distress Syndrome; Affect; Basic Science; Blood Cells; Blood Platelets; Blood specimen; Bronchoalveolar Lavage Fluid; Characteristics; Clinical; Coagulants; Coagulation Process; Code; Critical Care; Critical Illness; Data; Deposition; Development; Disease; Enrollment; Event; Fibrin; Fibrinogen; Functional disorder; Gene Expression; Gene Expression Profile; Generations; Histologic; Hospitals; Human; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukins; International; Introns; Investigation; Knowledge; Leukocytes; Life; Lung; Mediator of activation protein; Medical center; Megakaryocytes; Membrane; Messenger RNA; Molecular; Molecular Target; Neutropenia; Organ failure; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Physiological; Proteins; Public Health; Pulmonary Gas Exchange; RNA Splicing; RNA, Messenger, Splicing; Randomized; Reporting; Risk; Risk Factors; Role; Sampling; Sepsis; Severity of illness; Signal Transduction; Societies; Specimen; Spliceosomes; Therapeutic Intervention; Thrombin; Thromboplastin; Thrombopoiesis; Thrombosis; Time Study; Transcript; Translating; Universities; Utah; Ventilator; Work; abstracting; base; cytokine; healthy volunteer; indexing; insight; lead-binding proteins; lung injury; mRNA Expression; mRNA Precursor; monocyte; mortality; neutrophil; novel; prospective; respiratory; response

DESCRIPTION (provided by applicant): Acute lung injury (ALI), a common and often lethal illness, is characterized by widespread and injurious inflammation. Many features of ALI, including its pathophysiology and therapeutic interventions remain incompletely defined, in part because the cellular and molecular mechanisms are poorly understood. Although the role of leukocytes in ALI has been well studied, investigations into platelet function in ALI have been relatively infrequent and there are many gaps in our knowledge. Recent evidence from our group and others suggests that platelets have important functions that contribute to the development and progression of ALI. Platelets are known to possess a transcriptome of messenger RNAs (mRNAs) that they receive from megakaryocytes. Unexpectedly, we recently demonstrated that megakaryocytes also transfer intron- containing pre-mRNAs to platelets. In response to activating signals, anucleate platelets splice these pre-mRNAs and reassembled them into mature mRNA transcripts which are translated into functional proteins. Two of the spliced mRNAs we have characterized code for interleukin-1¿ (IL-1¿), an inflammatory cytokine, and tissue factor (TF), a regulator of coagulation. Both synthesized proteins have functional activity central to the pathobiology of ALI. In our preliminary data from sepsis patients (a risk factor for ALI), we demonstrated that the incidence of TF pre-mRNA splicing in platelets is markedly increased and predicts greater illness severity and higher mortality risk. These pilot data suggest a role for platelet-derived pre-mRNA splicing events in ALI. We now propose integrated clinical and basic science studies to explore these observations. A central hypothesis is that pre-mRNA splicing events in platelets are dysregulated in ALI, and that the expression of spliced messages in platelets provides predictive information in addition to contributing to pathologic sequellae. Two integrated specific aims will examine splicing patterns in (1) patients with ALI and (2) patients at-risk for ALI. These studies will generate new insights into the molecular pathobiology of ALI and may provide new targets for therapeutic interventions. Acute lung injury is a common disorder that results when the body's responses to infection become uncontrolled. Acute lung injury has high mortality and is a major public health issue. The studies proposed in this application explore newly-identified cellular and molecular mechanisms using samples from patients with this disorder and may yield new ways to chart the course of acute lung injury in individual patients, and have the potential to identify new molecular targets for therapeutic intervention. (End of Abstract)

描述（由申请人提供）： 急性肺损伤 (ALI) 是一种常见且常常致命的疾病，其特征是广泛的损伤性炎症，包括其病理生理学和治疗干预措施仍不完全明确，部分原因是对其细胞和分子机制知之甚少。白细胞在 ALI 中的作用已得到充分研究，但对 ALI 中血小板功能的研究相对较少，我们小组和其他人的最新证据表明，血小板具有促进 ALI 发生和发展的重要功能。众所周知，血小板拥有从巨核细胞接收的信使 RNA (mRNA) 转录组，我们最近证明巨核细胞也将含有内含子的前 mRNA 转移到血小板，以响应激活信号，使血小板剪接。这些前体 mRNA 并将它们重新组装成成熟的 mRNA 转录物，这些转录物被翻译成功能性蛋白质，我们已经确定了其中两个剪接的 mRNA 的编码。白细胞介素-1¿ (IL-1¿)，一种炎症细胞因子，和组织因子 (TF)，一种凝血调节剂。根据我们来自脓毒症患者的初步数据（ALI 的危险因素），这两种合成蛋白都具有重要的功能活性。 ，我们证明血小板中 TF 前体 mRNA 剪接的发生率显着增加，并预示着更大的疾病严重程度和更高的死亡风险。这些试验数据表明血小板衍生的前体 mRNA 剪接事件在中的作用。我们现在提出综合临床和基础科学研究来探索这些观察结果，一个中心假设是，血小板中的前 mRNA 剪接事件在 ALI 中失调，并且血小板中剪接信息的表达除了提供预测信息之外，还提供了预测信息。两个综合的具体目标将检查 (1) ALI 患者和 (2) 有 ALI 风险的患者的剪接模式，这些研究将为 ALI 的分子病理学提供新的见解，并可能为治疗提供新的靶点。急性肺损伤是一种常见疾病，当身体对感染的反应不受控制时会导致急性肺损伤，并且是一个主要的公共卫生问题。本申请中提出的研究利用新发现的细胞和分子机制。这种疾病患者的样本可能会产生新的方法来绘制个体患者的急性肺损伤病程，并有可能确定治疗干预的新分子靶标（摘要结束）。