Genomic analysis of pediatric SIRS and septic shock

儿科 SIRS 和感染性休克的基因组分析

• 批准号: 7827547
• 负责人: HECTOR R. WONG
• 金额: $ 27.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827547
• 关键词: Adult; Animals; Back; Biological; Biological Process; Biology; Bismuth; Blood; Blood specimen; Calibration; Characteristics; Child; Child health care; Childhood; Clinical; Cohort Studies; Collaborations; Contracts; Coupling; Critical Illness; Critically ill children; Data; Deposition; Detection; Development; Electrodes; Engineering; Enrollment; Environmental Exposure; Future; Gene Expression Profiling; Genomics; Goals; Heavy Metals; Homeostasis; Ions; Iron; Laboratories; Laboratory Study; Lead; Liquid substance; Literature; Manganese; Measurement; Measures; Metals; Methods; Microfluidics; Oxidative Stress; Pathology; Patients; Performance; Physiological; Play; Population; Reader; Recording of previous events; Recovery; Reference Standards; Role; Sampling; Scanning; Septic Shock; Series; Serum; Signal Transduction; Stress; Study Subject; Supplementation; Survivors; System; Technology; Testing; Therapeutic; Time; Translational Research; Universities; Validation; Whole Blood; Wound Healing; Zinc; base; biological adaptation to stress; blood glucose regulation; clinical application; cohort; commercialization; cost; follow-up; gene repression; immune function; instrument; large scale production; meetings; micro-total analysis system; parent grant; point of care; programs; public health relevance; research study; response; sensor; skills; stem; volunteer

DESCRIPTION (provided by applicant): This application is a competitive revision of the parent grant R01GM064619 and is being submitted in response to notice # NOT-OD-09-058. The competitive revision seeks to develop a point-of-care platform for measuring serum zinc concentrations in children with septic shock, the "zinc chip." The rationale for development of the zinc chip stems directly from data generated through the translational research program supported by the above parent grant. We have been conducting gene expression profiling studies (microarray) in children with septic shock. An unexpected finding is that pediatric septic shock is characterized by widespread and persistent repression of genes having functional annotations related to zinc biology. Functional validation of these data demonstrated that non-survivors of pediatric septic shock have abnormally low serum zinc concentrations compared to survivors. These data suggest that altered zinc homeostasis plays a role in the pathobiology of pediatric septic shock, and this assertion is well supported by a series of follow-up clinical and laboratory studies. Thus, we hypothesize that zinc supplementation may be an effective therapeutic strategy in pediatric septic shock, and are preparing to directly test this hypothesis by conducting zinc supplementation studies in critically ill children with septic shock. An important component for carrying out these studies in a safe and rigorous manner will be the capability to reliably and efficiently measure serum zinc concentrations in these patients. Current methods for measuring zinc are accurate, but costly and time consuming. Accordingly, we are proposing to develop a point-of-care platform to efficiently and accurately measure serum zinc concentrations. The zinc chip will be developed in collaboration with the University of Cincinnati Department of Engineering, which has a rich history of developing point-of-care platforms for clinical application, including the ability to measure heavy metals in biological fluids. The zinc chip will first be tested using donor serum samples spiked with known concentrations of zinc (Specific Aim 1). In Specific Aim 2 we will test the precision and accuracy of the zinc chip at the bedside of critically ill children by comparing zinc chip-derived measurements with reference laboratory data. We expect that successful development of the zinc chip will be an important advance in the safe and efficient conduct of the aforementioned zinc supplementation trials. This competitive revision meets the goals of the Recovery Act to stimulate the economy in two ways. In the short term, it will allow us to contract for additional needed skills by collaborating with the University of Cincinnati Department of Engineering to develop the zinc chip. In the long-term, development of the zinc chip will require larger scale production and could therefore lead to commercialization. Public health Relevance: The deliverable of this program will be the development of point-of-care platform for accurate and rapid measurement of serum zinc concentrations in critically ill children, the zinc chip. Child health will be positively impacted by developing the capability of conducting zinc supplementation trials in a safe and rigorous manner.

描述（由申请人提供）：此申请是对父母赠款R01GM064619的竞争性修订，并正在响应通知＃NOT-OD-09-058提交。竞争性的修订旨在开发一个保健平台，用于测量败血性休克儿童“锌芯片”的血清锌浓度。锌芯片开发的基本原理直接源于上述父母赠款支持的转化研究计划产生的数据。我们一直在进行败血性休克儿童中进行基因表达分析研究（微阵列）。一个出乎意料的发现是，小儿败血性休克的特征是对与锌生物学相关的功能注释的基因的广泛抑制和持续抑制。这些数据的功能验证表明，与幸存者相比，小儿败血性休克的非活体血清锌浓度异常低。这些数据表明，改变的锌体内平衡在小儿败血性休克的病理学中起作用，这一主张得到了一系列随访的临床和实验室研究的很好的支持。因此，我们假设补充锌可能是小儿败血性休克的有效治疗策略，并准备通过在患有败血性休克的重症儿童中进行锌补充研究直接检验该假设。以安全而严格的方式进行这些研究的重要组成部分是能够可靠，有效地测量这些患者的血清锌浓度的能力。当前测量锌的方法是准确的，但昂贵且耗时。因此，我们建议开发一个护理平台，以有效，准确地测量血清锌浓度。锌芯片将与辛辛那提大学工程系合作开发，该系具有悠久的历史，即开发用于临床应用的护理点平台，包括测量生物流体中重金属的能力。锌芯片将首先使用含有已知锌浓度的供体血清样品进行测试（特定AIM 1）。在特定目标2中，我们将通过将锌芯片衍生的测量结果与参考实验室数据进行比较，测试重症儿童床边的锌芯片的精确性和准确性。我们预计，在上述补充锌补充试验的安全有效行为中，锌芯片的成功开发将是重要的进步。这项竞争性修订符合以两种方式刺激经济的恢复法案的目标。在短期内，通过与辛辛那提大学工程系开发锌芯片的合作，我们将允许我们签订额外的所需技能。从长远来看，锌芯片的开发将需要大规模生产，因此可能导致商业化。 公共卫生相关性：该计划的可交付将是保健点平台的开发，以准确，快速测量重症儿童锌芯片的血清锌浓度。儿童健康将受到以安全和严格的方式发展补充锌试验的能力的积极影响。

项目成果

Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype.

• DOI: 10.1097/ccm.0000000000001852
• 发表时间: 2016-11
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Wong HR;Cvijanovich NZ;Anas N;Allen GL;Thomas NJ;Bigham MT;Weiss SL;Fitzgerald J;Checchia PA;Meyer K;Quasney M;Hall M;Gedeit R;Freishtat RJ;Nowak J;Raj SS;Gertz S;Howard K;Harmon K;Lahni P;Frank E;Hart KW;Nguyen TC;Lindsell CJ
• 通讯作者: Lindsell CJ

Clinical review: sepsis and septic shock--the potential of gene arrays.

• DOI: 10.1186/cc10537
• 发表时间: 2012-02-08
• 期刊: Critical care (London, England)
• 作者: Wong HR

Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children.

• DOI: 10.1186/cc11847
• 发表时间: 2012-10-29
• 期刊: Critical care (London, England)
• 作者: Wong HR;Cvijanovich NZ;Hall M;Allen GL;Thomas NJ;Freishtat RJ;Anas N;Meyer K;Checchia PA;Lin R;Bigham MT;Sen A;Nowak J;Quasney M;Henricksen JW;Chopra A;Banschbach S;Beckman E;Harmon K;Lahni P;Shanley TP
• 通讯作者: Shanley TP

Biomarkers for pediatric sepsis and septic shock.

• DOI: 10.1586/eri.10.154
• 发表时间: 2011-01
• 期刊: Expert review of anti-infective therapy
• 影响因子: 5.7
• 作者: Standage SW;Wong HR
• 通讯作者: Wong HR

Identification of pediatric septic shock subclasses based on genome-wide expression profiling.

• DOI: 10.1186/1741-7015-7-34
• 发表时间: 2009-07-22
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Wong HR;Cvijanovich N;Lin R;Allen GL;Thomas NJ;Willson DF;Freishtat RJ;Anas N;Meyer K;Checchia PA;Monaco M;Odom K;Shanley TP
• 通讯作者: Shanley TP