Lactoferrin for Immunomodulation of Systemic Inflammatory Response Syndrome

乳铁蛋白用于全身炎症反应综合征的免疫调节

基本信息

批准号：
8131596
负责人：
JEFFREY K ACTOR
金额：
$ 73.8万
依托单位：
PHARMAREVIEW CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8131596
关键词：
Acute Address Adjuvant Animal Model Animals Antibiotic Therapy Attention Automobile Driving Bacteria Bacterial Infections Bacterial Translocation Biological Biological Markers Biological Models Biological Process Blood Circulation Canis familiaris Cause of Death Cell Line Cellular Immunity Clinical Clinical Protocols Collaborations Complex Computer software Containment DNA Damage Data Development Diagnosis Distant Dose Drug Kinetics Effectiveness Endotoxemia Ensure Enzyme-Linked Immunosorbent Assay Escherichia coli Etiology Event Gene Expression Gene Mutation General Population Genes Goals Gram-Negative Bacteria Gram-Positive Bacteria Gram-Positive Bacterial Infections Health Health Services Research Histologic Histology Homeostasis Hospitals Human Human Milk Immune In Vitro Infection Inflammation Inflammation Mediators Inflammatory Response Intensive Care Units Interleukin-6 Intestines Kidney Laboratories Lactoferrin Life Lipopolysaccharides Liver Lung Measurement Measures Mediating Mediation Mediator of activation protein Microarray Analysis Mitochondrial DNA Molecular Molecular Profiling Multiple Organ Failure Mus N-terminal Nature Nebraska Neuraminic Acids Nitric Oxide Non-Rodent Model Nosocomial Infections Ohio Organ Organism Oxidative Stress Pathway Analysis Pathway interactions Pattern Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Physiological Pichia Play Polymerase Chain Reaction Predisposition Prevention Primary Cell Cultures Procedures Production Property Protocols documentation Quality Control RNA Rattus Recombinants Relative (related person)Research Rodent Rodent Model Role Safety Sepsis Sepsis Syndrome Septic Shock Septicemia Serum Small Business Technology Transfer Research Species Specificity Staging Staining method Stains Staphylococcus aureus Structure Symptoms System TNF gene Testing Texas Therapeutic Therapeutic Intervention Time Tissues Toxic effect Toxicity Tests Toxicokinetics Toxicology Universities Use Effectiveness Virulence Western Blotting Work Yeasts base chemokine combat commercialization design drug development efficacy testing genotoxicity glycosylation immunogenicity immunopathology immunoregulation medical schools meetings methicillin resistant Staphylococcus aureus mitochondrial dysfunction molecular marker mortality neutrophil novel phase 1 study phase 2 study pre-clinical prevent prophylactic protective effect research study response septic stressor therapeutic development

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a biologic therapeutic to treat systemic inflammatory response syndrome (SIRS) using a novel human recombinant lactoferrin that contains "humanized" glycosylation patterns. SIRS is a clinical expression of the action of complex acute-phase intrinsic mediators that precedes sepsis and subsequent tissue damage leading to Multiple Organ Failure. The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. There is a great need for development of therapeutics to combat SIRS before its progression to sepsis. During sepsis, immune homeostasis is lost leading to destructive immunopathology. This proposal will examine lactoferrin's effects to mediate cellular responses during the development of bacterial-induced systemic inflammation in mice. Focus will be made on utility of rhLF, with dose range comparisons made to commercially available human milk- and neutrophil-derived lactoferrins. A battery of tests will be employed to include measurement of pro-inflammatory mediators and gene expression profiles following specific bacterial insult. The systemic events associated with lactoferrin mediation will also be investigated using methicillin-resistant Staphylococcus aureus bacteria (MRSA) infection, which is troublesome in hospital-associated (nosocomial) infections. There is a defined need to address development of therapeutics and cautionary procedures to ensure containment within the general population. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from both Gram-negative bacteria, as well as Gram-positive bacteria such as Staphylococcus aureus. PUBLIC HEALTH RELEVANCE: The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. SIRS describes the clinical manifestations derived from an acute nonspecific illness preceding septicemia, whereas an infectious etiology is required for the exact diagnosis of sepsis. There is a great need for development of therapeutics to address the early stages of insult-induced inflammation and to prevent its progression. In particular, this become an important issue with both Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which is troublesome in hospital-associated (nosocomial) infections. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from Gram-positive bacteria, such as Staphylococcus aureus, as well as from Gram-negative entities. The goal of this proposal is to examine the utility of a novel human recombinant Lactoferrin to combat SIRS, and limit progression of SIRS.

描述（由申请人提供）：该项目的总体目标是开发一种生物疗法，使用含有“人源化”糖基化模式的新型人重组乳铁蛋白来治疗全身炎症反应综合征（SIRS）。 SIRS 是败血症和随后导致多器官衰竭的组织损伤之前复杂急性期内在介质作用的临床表现。全身炎症反应综合征 (SIRS) 是脓毒症的先兆，被认为是重症监护病房死亡的主要原因，死亡率在 30% 至 90% 之间。非常需要开发治疗方法来在 SIRS 发展为脓毒症之前对抗它。在脓毒症期间，免疫稳态丧失，导致破坏性免疫病理学。该提案将研究乳铁蛋白在小鼠细菌诱导的全身炎症发展过程中介导细胞反应的作用。重点将放在 rhLF 的实用性上，并与市售的母乳和中性粒细胞衍生的乳铁蛋白进行剂量范围比较。将采用一系列测试来测量促炎介质和特定细菌损伤后的基因表达谱。还将使用耐甲氧西林金黄色葡萄球菌 (MRSA) 感染来研究与乳铁蛋白介导相关的全身事件，这在医院相关（院内）感染中很麻烦。明确需要解决治疗方法和警示程序的开发，以确保在普通人群中进行遏制。事实上，开发一种新策略（增强抗生素治疗）来控制革兰氏阴性菌和革兰氏阳性菌（如金黄色葡萄球菌）发生的 SIRS 的需求尚未得到满足。公共卫生相关性：全身炎症反应综合征 (SIRS) 是脓毒症的先兆，并且被认为是重症监护病房的主要原因，死亡率为 30% 至 90%。 SIRS 描述了败血症之前的急性非特异性疾病的临床表现，而脓毒症的准确诊断需要感染性病因。非常需要开发治疗方法来解决损伤引起的炎症的早期阶段并防止其进展。特别是，这成为革兰氏阴性和革兰氏阳性细菌的一个重要问题，包括耐甲氧西林金黄色葡萄球菌（MRSA），它在医院相关（院内）感染中很麻烦。事实上，开发一种新策略（增强抗生素治疗）来控制金黄色葡萄球菌等革兰氏阳性菌以及革兰氏阴性菌引起的 SIRS 的需求尚未得到满足。该提案的目的是研究新型人重组乳铁蛋白对抗 SIRS 并限制 SIRS 进展的效用。