Supplement for MIRA award_Wong_2021

MIRA 奖补充材料_Wong_2021

• 批准号: 10389655
• 负责人: HECTOR R. WONG
• 金额: $ 7.7万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389655
• 关键词: Adolescent; Adult; Age; Award; Back; Basic Science; Biological; Biological databases; Child; Childhood; Clinical; Clinical Data; Clinical Research; Collaborations; Critical Care; Data; Databases; Development; Diagnosis; Diagnostic; Failure; Foundations; Heterogeneity; Immune response; Investigation; Laboratories; Measures; Medicine; Multicenter Studies; National Institute of General Medical Sciences; Outcome; Pathway interactions; Patient Care; Phenotype; Public Health; Research; Research Personnel; Risk; Sampling; Sepsis; Testing; Training; Training Programs; Translational Research; Translations; base; bench to bedside; catalyst; clinical database; clinically relevant; data repository; genome-wide; mouse model; new therapeutic target; novel therapeutics; outcome prediction; pathogen; prognostic; programs; repository; response; stem; transcriptomics; translational study; validation studies

ABSTRACT (original application) Sepsis continues to be a major, worldwide public health problem in both adults and children. Heterogeneity at multiple levels is an important aspect of clinical sepsis. There are many major gaps in the field directly stemming from this heterogeneity. There is a need to better understand the fundamental host responses to sepsis, the pathways to host failure, and to identify novel therapeutic targets. There is a need to understand how developmental age influences the host response to sepsis. There is a need to more reliably diagnose sepsis, including earlier pathogen class identification. There is a need to effectively predict outcomes and assess how the risks for bad outcomes change in response to both current and novel therapies. There is a need to characterize biological and phenotypic subclasses (endotypes) of sepsis, and how those endotypes differentially respond to therapies. In short, there is a need to better account for the intrinsic heterogeneity of sepsis when caring for patients and when conducting research. Accordingly, the operational themes of this proposal are measuring and understanding sepsis heterogeneity through basic and translational research using a bedside to bench to bedside approach. Since 2004, we have led a multi-center study to create, maintain, and grow a robust repository of biological samples combined with comprehensive clinical data for children with sepsis. Using genome-wide, discovery-oriented, transcriptomic studies as the foundation, we have leveraged this database for various discoveries having direct translational potential to the bedside. We have also leveraged these data to expand our studies to adults with sepsis in collaboration with a number of investigators based in adult critical care medicine. The laboratory is actively engaged in basic research involving adult and pediatric murine models of sepsis, thus providing a robust testing ground for our clinical discoveries and observations. In fact, all of our current and planned laboratory-based research efforts are driven by discoveries generated from our clinical and biological database of children with sepsis. The laboratory also supports a NIGMS-sponsored T32 training program that is currently in its 24th year of existence, and for which the PI serves as the Co-Program Director. We propose a program of research that encompasses the full range of translation, from bedside to bench to bedside. Our clinical and biological data repository will be leveraged to generate hypotheses about the pathobiology of sepsis that will be tested in murine models and subsequently brought back to the bedside to advance diagnostic, prognostic, and treatment approaches in sepsis. This framework provides a strong foundation for collaboration and training and will continue to be a catalyst for new investigations and new investigators alike.

摘要（原始申请） 脓毒症仍然是成人和儿童的主要全球公共卫生问题。异质性 多水平是临床脓毒症的一个重要方面。直接在该领域存在许多重大空白 源于这种异质性。有必要更好地了解宿主对 脓毒症，宿主衰竭的途径，并确定新的治疗靶点。有必要了解 发育年龄如何影响宿主对败血症的反应需要更可靠地诊断 败血症，包括早期病原体分类鉴定。需要有效地预测结果， 评估不良结局的风险如何随着当前和新疗法的变化而变化。有一个 需要表征脓毒症的生物学和表型亚类（内型），以及这些内型如何 对治疗有不同的反应简而言之，需要更好地解释 脓毒症时照顾病人和进行研究。因此，本报告的业务主题 建议通过基础和转化研究来测量和理解脓毒症异质性 从床边到长凳再到床边自2004年以来，我们领导了一项多中心研究， 维护和发展一个强大的生物样本库，并结合全面的临床数据， 败血症的孩子使用全基因组，以发现为导向，转录组学研究为基础，我们 已经利用这个数据库的各种发现，具有直接转化为临床的潜力。我们 我还利用这些数据，与一些研究人员合作，将我们的研究扩展到患有败血症的成年人。 成人重症监护医学的研究人员。该实验室积极从事基础研究 包括成人和小儿败血症小鼠模型，从而为我们的临床研究提供了一个强大的测试基础。 发现和观察。事实上，我们所有目前和计划中的实验室研究工作都是 由我们的败血症儿童临床和生物学数据库中的发现驱动。的 实验室还支持NIGMS赞助的T32培训计划，该计划目前已存在24年， PI担任联合项目总监。我们提出了一个研究计划， 全方位的翻译，从床边到长凳再到床边。我们的临床和生物学数据库将 用于产生关于脓毒症病理生物学的假设，这些假设将在鼠模型中进行测试， 随后被带回床边，以推进诊断，预后和治疗方法， 败血症这一框架为合作和培训提供了坚实的基础，并将继续成为一个 新调查的催化剂和新的调查人员一样。

项目成果

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

• DOI: 10.1186/s13054-023-04535-1
• 发表时间: 2023-06-26
• 期刊: Critical care (London, England)
• 作者: Atreya MR;Cvijanovich NZ;Fitzgerald JC;Weiss SL;Bigham MT;Jain PN;Schwarz AJ;Lutfi R;Nowak J;Allen GL;Thomas NJ;Grunwell JR;Baines T;Quasney M;Haileselassie B;Alder MN;Lahni P;Ripberger S;Ekunwe A;Campbell KR;Walley KR;Standage SW
• 通讯作者: Standage SW