权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Resistance of Beta 2 Microglobulin Null Mice to Sepsis

Beta 2 微球蛋白无效小鼠对脓毒症的抵抗力

基本信息

批准号：
7256520
负责人：
EDWARD R SHERWOOD
金额：
$ 25.06万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7256520
关键词：
Acid-Base Equilibrium Acute Adoptive Transfer Affect Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens Bacterial Counts Blocking Antibodies CD1 Antigens CD8B1 gene Cardiovascular Physiology Cardiovascular system Cell physiology Cells Cessation of life Class Clinical Cytolysis Disease End Point Enzymes Evaluation Exhibits Flow Cytometry Functional disorder Goals Granzyme Heart IL8 gene Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interferons Interleukin-1 Interleukin-6 Intra-abdominal Knock-out Knockout Mice Ligation Liver Lung Major Histocompatibility Complex Measures Mediating Mediator of activation protein Mining Modeling Mus Natural Killer Cells Numbers Organ Pathogenesis Pathway interactions Peritoneal Peritoneal Fluid Peritonitis Physiological Play Population Probability Process Production Proteins Puncture procedure Rate Reading Research Research Design Research Personnel Research Project Grants Resistance Resources Role Sepsis Septic Shock Serum Spleen T-Lymphocyte Testing Treatment Effectiveness beta-2 Microglobulin cell injury cell type chemokine cytokine design granzyme A improved indexing killer T cell mortality perforin porin programs response septic

项目摘要

DESCRIPTION (provided by applicant): Beta2 microglobulin knockout mice are deficient in CD8+ T cells and natural killer T cells. Compared to wild type mice, beta2 microglobulin knockout mice exhibit improved survival during sepsis caused by cecal ligation and puncture (CLP). Further depletion of natural killer cells by injection of anti-asialoGM1 confers near complete resistance to CLP-induced mortality. The mechanisms underlying these observations are unknown. However, two potential mechanisms have high probability. Firstly, CD8+ T, natural killer T and natural killer cells can impact innate immune responses by amplifying production of pro-inflammatory cytokines and chemokines. These cell populations can also cause direct cellular injury during inflammation. Therefore, it is hypothesized that CD8+ T, natural killer T and natural killer cells facilitate or directly mediate sepsis-induced mortality by amplifying the pro-inflammatory response and/or causing direct cellular injury. Secondly, beta2 microgiobulin comprises the beta chain of the class I major histocompatibility complex and the non-classical antigen-presenting molecule CD1. Both of these molecules are important for presentation of self and foreign antigens, respectively, but their roles in regulating inflammatory responses during sepsis are unknown. It is further hypothesized that the class I major histocompatibility complex, CD1 and/or unrecognized beta2 microglobulin-associated molecules play a role in modulating the immune response during sepsis. This research project is designed to test these hypotheses. The following specific aims are proposed: Aim 1: To determine the specific contributions of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 to the pathogenesis of lethal intra-abdominal sepsis. Mortality, bacterial counts, organ injury, cardiovascular function and acid-base balance will be measured following CLP in control mice and mice that are deficient in these cell populations and antigen-presenting molecules. Specific Aim 2: To determine the functional roles of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 in regulating the pro-inflammatory response during lethal intra-abdominal sepsis. Intra-abdominal and systemic cytokine and chemokine production will be measured following CLP in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1. Specific Aim 3: To determine the role of cytolytic mechanisms in the pathogenesis of lethal intra-abdominal sepsis. We will evaluate expression of perforin, granzymes, Fas and FasL in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells after CLP. The functional roles of the perforin/granzyme and Fas-FasL pathways will be determined by assessing survival, cardiovascular function, organ injury and acid-base balance in perforin-deficient and FasL-deficient mice. These studies are designed to define new mechanisms that are important in the pathogenesis of septic shock with the ultimate goal of developing new treatments for this lethal disease process.

描述（由申请人提供）：