Bcl-2 induced protection in severe sepsis

Bcl-2 在严重脓毒症中诱导保护

基本信息

批准号：
7522786
负责人：
ROBERT K WINN
金额：
$ 111.47万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7522786
关键词：
Activated Lymphocyte Adult Adult Respiratory Distress Syndrome Antibodies Apoptotic B-Lymphocytes CD3 Antigens Candidate Disease Gene Caring Cause of Death Cells Clinical Clinical Trials Complication Coupled Critical Illness Data Development Disease Doctor of Philosophy Epithelial Cells Failure Gene Expression Genes Healthcare Inflammation Investigation Life Ligation Lung Lymphocyte Mature Lymphocyte Methods Microarray Analysis Monoclonal Antibodies Multiple Organ Failure Mus Myeloid Cells Newborn Respiratory Distress Syndrome Numbers Other Therapy Outcome Patients Peritoneal Peritoneum Pharmaceutical Preparations Proteins Proteomics Publications Puncture procedure Research Sepsis Sepsis Syndrome T-Lymphocyte Therapeutic Transplantation United States Viral Vector activated Protein C base improved mortality pre-clinical preclinical study programs research study septic

项目摘要

Sepsis and/or sepsis syndrome constitutes a major cause of death in critically ill patients and mortality remains high despite advances in clinical care. Sepsis is the best single predictor for development of the Adult Respiratory Distress Syndrome (ARDS). The high mortality in sepsis coupled with the disappointing results from recent clinical trials demonstrates a continuing need for new methods of treating this disease. Recent publications have shown that over-expression of the anti-apoptotic molecule Bcl-2 in T-lymphocytes, B-lymphocytes and in gut epithelial cells results in increased survival in mouse sepsis resulting from cecal ligation and puncture (CLP). We show in preliminary experiments that over-expression of Bcl-2 in myeloid cells also provides protection in sepsis resulting from CLP and that this protection can be adoptively transferred through transplanting Bcl-2 myeloid cells into mice deficient in mature lymphocytes (Rag-/-). These data suggest that lymphocytes are not necessary for Bcl-2 over-expression to provide protection from CLP. The first hypothesis of this project states that over-expression of Bcl-2 induces the expression of a gene(s) whose product(s) is protective in severe sepsis. Additional preliminary results show that T-lymphocytes from normal mice when adoptively transferred to the peritoneum can provide protection from CLP when previously stimulated with antibodies to either CD3 or CD90. Thus our second hypothesis states that stimulation of T-lymphocytes with antibodies to either CD3 or CD90 results in expression of cyto-protective gene(s) and their product(s) provides protection from severe sepsis. We will investigate these hypotheses through the following specific aims. 1) To identify candidate gene(s) whose product(s) may be protective in severe sepsis by comparing gene expression between controls and Bcl-2 over-expressing myeloid cells, T-lymphocytes and B-lymphocytes using gene expression arrays. 2) To identify candidate gene(s) whose product(s) may be protective in severe sepsis by comparing gene expression between unstimulated T-lymphocytes and lymphocytes stimulated by monoclonal antibodies that recognize CD3 or CD90. 3) To examine the efficacy in sepsis of candidate protective genes as determined by either microarray analysis or by the proteomics approach in specific aims 1 and 2.

败血症和/或败血症综合征构成了重症患者的主要死亡原因，尽管临床护理的进步取得了进步，死亡率仍然很高。败血症是成人呼吸窘迫综合征（ARDS）发展的最佳单一预测因子。败血症的高死亡率加上最近的临床试验令人失望的结果表明，对治疗这种疾病的新方法的持续需求。最近的出版物表明，在T淋巴细胞，B淋巴细胞和肠道上皮细胞中，抗凋亡分子Bcl-2的过表达导致小鼠败血症的存活率增加，导致CECAL结扎和刺穿（CLP）。我们在初步实验中表明，髓样细胞中Bcl-2的过表达还提供了由CLP引起的败血症的保护，并且可以通过移植Bcl-2髓样细胞转移到成熟的淋巴细胞（RAG-/ - ）中的小鼠中。这些数据表明，Bcl-2过表达不需要淋巴细胞提供CLP的保护。该项目的第一个假设指出，Bcl-2的过表达诱导其产物在严重败血症中具有保护性的基因的表达。其他初步结果表明，当通过采用转移到腹膜时，正常小鼠的T淋巴细胞在先前用抗CD3或CD90抗体刺激时可以提供保护不受CLP的保护。因此，我们的第二个假设指出，刺激具有抗CD3或CD90抗体的T淋巴细胞会导致细胞保护基因的表达及其产物可提供防止严重败血症的保护。我们将通过以下特定目标研究这些假设。 1）确定其产品可能是的候选基因使用基因表达阵列比较过表达的髓样细胞，T淋巴细胞和B淋巴细胞之间的对照和Bcl-2之间的基因表达，在严重的败血症中保护性。 2）通过比较识别CD3或CD90的单克隆抗体刺激的未刺激的T-淋巴细胞和淋巴细胞之间的基因表达，可以通过比较未刺激的T-淋巴细胞和淋巴细胞之间的基因表达来确定其在严重败血症中具有保护性的候选基因。 3）检查由微阵列分析或特定目的1和2中的蛋白质组学方法确定的候选保护基因败血症的功效。