Genomic analysis of pediatric SIRS and septic shock

描述(由申请人提供)：本申请是对R01GM064619号家长资助的竞争性修订，是对#NOT-OD-09-058号通知的回应。这项竞争性修订旨在开发一个用于测量感染性休克儿童血清锌浓度的护理点平台，即“锌芯片”。开发锌芯片的理由直接来自由上述父母拨款支持的翻译研究计划产生的数据。我们一直在进行感染性休克儿童的基因表达谱研究(微阵列)。一个意想不到的发现是，儿童感染性休克的特征是具有与锌生物学相关的功能注释的基因的广泛和持久的抑制。这些数据的功能验证表明，与幸存者相比，儿童感染性休克的死亡者血清锌浓度异常低。这些数据表明锌稳态改变在儿童感染性休克的病理生物学中起作用，这一断言得到了一系列后续临床和实验室研究的很好支持。因此，我们假设补锌可能是儿童感染性休克的有效治疗策略，并准备通过在感染性休克危重患儿中进行补锌研究来直接检验这一假设。以安全和严格的方式进行这些研究的一个重要组成部分将是能够可靠和有效地测量这些患者的血清锌浓度。目前测量锌的方法是准确的，但成本和时间都很长。因此，我们建议开发一个护理点平台，以有效和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，辛辛那提大学工程系在开发临床应用的护理点平台方面有着丰富的历史，包括测量生物液中重金属的能力。锌芯片将首先使用添加了已知锌浓度的捐赠者血清样本进行测试(特定目标1)。在具体目标2中，我们将通过将锌芯片的测量结果与参考实验室数据进行比较，来测试危重儿童床边锌芯片的精密度和准确性。我们预计，锌芯片的成功开发将是在安全和高效地进行上述补锌试验方面的重要进展。这一竞争性修订符合复苏法案的目标，即通过两种方式刺激经济。短期内，它将使我们能够通过与辛辛那提大学工程系合作开发锌芯片来合同获得更多所需的技能。从长远来看，锌芯片的开发将需要更大规模的生产，因此可能导致商业化。 公共卫生相关性：该项目的交付成果将是开发用于准确和快速测量危重儿童血清锌浓度的护理点平台，即锌芯片。发展以安全和严格的方式进行锌补充试验的能力将对儿童健康产生积极影响。

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.