TEMPORAL ANALYSIS OF PLATELETS AS CYTOTOXIC MEDIATORS IN SEPSIS

脓毒症中血小板作为细胞毒性介质的时间分析

• 批准号: 7951117
• 负责人: Robert J Freishtat
• 金额: $ 0.09万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7951117
• 关键词: Accounting; Acute Lung Injury; Biological Assay; Blood Platelets; Blood specimen; Categories; Cell Fraction; Cessation of life; Child; Clinical; Clinical Research; Collection; Computer Retrieval of Information on Scientific Projects Database; DNA; Databases; Development; Enrollment; Funding; Genetic; Genomics; Grant; Granzyme; Hour; Immune response; In Vitro; Individual; Infectious Agent; Institution; Lymphocyte; Mediator of activation protein; Molecular; Morbidity - disease rate; Participant; Patients; Pattern; Peripheral; Process; Recruitment Activity; Research; Research Personnel; Resources; Sampling; Sepsis; Sepsis Syndrome; Septic Shock; Source; Testing; United States National Institutes of Health; Whole Blood; base; cytotoxic; cytotoxicity; insight; killings; mortality; peripheral blood; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The body's response to an infectious or non-infectious insult has been termed the systemic inflammatory response syndrome (SIRS). When this process is known to be caused by an infectious agent, the terms sepsis and SIRS are synonymous. SIRS/sepsis and its sequelae, including Acute Lung Injury, remain a leading cause of morbidity and mortality in children. Based on new insights into the molecular processes of SIRS, we hypothesize that in children with SIRS, the progression to septic shock, MODS, and/or death, is associated with the variable expression patterns of platelet granzymes. Specific Aim 1: Development of a genomic database of children with SIRS, septic shock, and/or MODS and healthy controls. In order to test our central hypothesis, it will be necessary to establish a genetic and clinical database of 22 individuals to account for the anticipated diversity of host responses to SIRS. We propose to isolate cell fractions from concurrent collections of peripheral whole blood from 22 children with SIRS recruited from the CNMC PICU. Two samples will be obtained from each SIRS participant; one will be obtained at the onset of SIRS and then the other sample 48 hours after that. DNA will also be isolated from the blood samples. SIRS participants will be recruited from the CNMC PICU. In addition, a single peripheral blood sample will be collected from 20 healthy normal control children enrolled in the CNMC ED. Specific Aim 2: Perform functional in vitro lymphocyte killing assays on platelets from all enrolled patients in Aim 1. We will classify our patients according to the proposed categories: 1) controls, 2) SIRS alone, 3) SIRS progressing to septic shock/MODS, and 4) SIRS progressing to septic shock/MODS and death. Using the in vitro lymphocyte killing assays, we will determine the degree of cytotoxicity of each participant's platelets. Cytotoxicity in each of the proposed categories will be compared in order to test our central hypothesis that the progression from SIRS to septic shock, MODS, and/or death is dependent on the expression patterns of platelet granzymes.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 身体对感染性或非感染性损伤的反应被称为全身炎症反应综合征（SIRS）。 当已知该过程是由传染原引起时，术语脓毒症和 SIRS 是同义词。 SIRS/败血症及其后遗症，包括急性肺损伤，仍然是儿童发病和死亡的主要原因。基于对 SIRS 分子过程的新见解，我们假设 SIRS 儿童中脓毒性休克、MODS 和/或死亡的进展与血小板颗粒酶的可变表达模式有关。 具体目标 1：开发 SIRS、感染性休克和/或 MODS 儿童以及健康对照儿童的基因组数据库。 为了检验我们的中心假设，有必要建立一个包含 22 名个体的遗传和临床数据库，以解释宿主对 SIRS 反应的预期多样性。我们建议从 CNMC PICU 招募的 22 名 SIRS 儿童同时采集的外周全血中分离细胞组分。每个 SIRS 参与者都会获得两个样本；一份将在 SIRS 开始时获取，然后在 48 小时后获取另一份样本。 DNA 也将从血液样本中分离出来。 SIRS 参与者将从 CNMC PICU 招募。此外，还将从 CNMC 急诊科登记的 20 名健康正常对照儿童中采集一份外周血样本。 具体目标 2：对目标 1 中所有入组患者的血小板进行功能性体外淋巴细胞杀伤测定。我们将根据建议的类别对患者进行分类：1) 对照，2) 仅 SIRS，3) SIRS 进展为感染性休克/MODS和 4) SIRS 进展为感染性休克/MODS 和死亡。使用体外淋巴细胞杀伤试验，我们将确定每个参与者血小板的细胞毒性程度。将比较每个拟议类别的细胞毒性，以检验我们的中心假设，即从 SIRS 到感染性休克、MODS 和/或死亡的进展取决于血小板颗粒酶的表达模式。