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Clinical and Proteomic Characterization of Nucleosomes in Pediatric Acute Respiratory Distress Syndrome

小儿急性呼吸窘迫综合征核小体的临床和蛋白质组学特征

基本信息

批准号：
9922345
负责人：
Nadir Yehya
金额：
$ 14.79万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922345
关键词：
Acute Address Adult Adult Respiratory Distress Syndrome Affect Age Alveolar Basic Science Bilateral Blood Circulation Cell Culture Techniques Cell Nucleus Child Childhood Chromatin Clinical Clinical Research Cohort Studies Complex Critically ill children DNA Data Development Diagnosis Diffuse Endothelial Cells Epidemiology Epithelial Cells Etiology Exposure to Failure Goals Guidelines Heart failure Histones Hour Human Hypoxemia In Vitro Infection Infrastructure Intubation Knowledge Link Lung Inflammation Measures Mechanics Mediating Mediator of activation protein Mentorship Methods Nuclear Nucleosomes Organ failure Outcome Pathogenicity Pediatric Acute Respiratory Distress Syndrome Pediatric Hospitals Pediatric Intensive Care Units Pediatric cohort Pediatrics Pennsylvania Permeability Pharmacology Philadelphia Plasma Plasma Proteins Pneumonia Population Post Translational Modification Analysis Post-Translational Protein Processing Pre-Clinical Model Primary Cell Cultures Proteins Proteomics Pulmonary Edema Rattus Research Risk Rodent Model Role Sepsis Severity of illness Supportive care Syndrome Techniques Testing Time Tissues Training Translating Translational Research Trauma Uncertainty United States Universities cecal ligation puncture cell injury cell type cytotoxicity design effective therapy experience extracellular histone modification improved improved outcome in vivo in vivo evaluation inhibitor/antagonist insight lung injury mortality novel novel therapeutics pre-clinical septic skills therapeutic target translational scientist

项目摘要

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. The syndrome affects 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 30%. Infection is the leading cause of pediatric ARDS, with up to 80% of cases occurring in the setting of either infectious pneumonia or non-pulmonary sepsis. There are no specific pharmacological therapies for ARDS despite several trials, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are typically extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Recent evidence has implicated nucleosomes, the DNA/histone complexes released into circulation as a result of nuclear chromatin degradation after cellular damage, as pathogenic in systemic sepsis and trauma-associated ARDS in adults. Normally located within the nucleus, nucleosomes released into the circulation are toxic to multiple cell types, offering a novel mechanism linking diverse inciting insults with subsequent lung injury. However, whether nucleosomes are pathogenic in pediatric ARDS is unknown. The broad objectives of this proposal are to 1) determine the association between nucleosome levels and outcomes in a cohort of pediatric ARDS; 2) determine the composition of the pathogenic nucleosomes by identifying specific histones and associated post-translational modifications; 3) demonstrate the pathogenicity of post-translationally modified and unmodified histones in in vitro cell culture and in vivo rodent models; and 4) develop the skills necessary to become a successful translational scientist in pediatric lung injury by focused training in epidemiology and proteomics. The proposed studies leverage existing infrastructure at the Children’s Hospital of Philadelphia and University of Pennsylvania to conduct a cohort study in pediatric ARDS and to perform novel proteomic analyses. A diverse and experienced mentorship team, with expertise in basic, translational, and clinical research, has been assembled to provide guidance through a rigorous training plan involving research conduct, didactics in advanced epidemiological analyses and proteomics, and intensive mentorship. The proposed studies will establish the relevance of plasma nucleosomes in pediatric ARDS, provide a novel technique for isolating and analyzing nucleosome-associated proteins, and improve our understanding of the pathogenicity of circulating histones. We will use these insights to study novel therapies for ARDS, and I will gain the necessary training in clinical research and proteomics to mature into an independent translational scientist working to improve outcomes for critically ill children.

项目总结/文摘

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pediatric ARDS biomarkers: missing the random forest for the trees.

儿科 ARDS 生物标志物：只见树木不见随机森林。

DOI：
10.1186/s13054-019-2396-7
发表时间：
2019
期刊：
Critical care (London, England)
影响因子：
0
作者：
Yehya,Nadir
通讯作者：
Yehya,Nadir

High frequency percussive ventilation in pediatric acute respiratory failure.

DOI：
10.1002/ppul.25191
发表时间：
2021-03
期刊：
Pediatric pulmonology
影响因子：
3.1
作者：
Butler AD;Dominick CL;Yehya N
通讯作者：
Yehya N

Differentiating children with sepsis with and without acute respiratory distress syndrome using proteomics.

使用蛋白质组学区分患有或不患有急性呼吸窘迫综合征的脓毒症儿童。

DOI：
10.1152/ajplung.00164.2021
发表时间：
2022
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Yehya,Nadir;Fazelinia,Hossein;Taylor,DeanneM;Lawrence,GladysG;Spruce,LynnA;Thompson,JillM;Margulies,SusanS;Seeholzer,StevenH;Worthen,GScott
通讯作者：
Worthen,GScott

Prevalence of gender dysphoria and suicidality and self-harm in a national database of paediatric inpatients in the USA: a population-based, serial cross-sectional study.

DOI：
10.1016/s2352-4642(22)00280-2
发表时间：
2022-12
期刊：
LANCET CHILD & ADOLESCENT HEALTH
影响因子：
36.4
作者：
Mitchell, Hannah K.;Keim, Garrett;Apple, Danielle E.;Lett, Elle;Zisk, Annie;Dowshen, Nadia L.;Yehya, Nadir
通讯作者：
Yehya, Nadir

Professionalism in pediatric anesthesiology: Affirmation of a definition based on results of a nationally administered survey of pediatric anesthesiologists.

儿科麻醉学的专业性：根据全国儿科麻醉师调查结果确认定义。