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Engineered chemokines as therapeutics for bacterial infections

工程化趋化因子作为细菌感染的治疗方法

基本信息

批准号：
10008136
负责人：
ASHOK K CHOPRA
金额：
$ 6.54万
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：
2018
资助国家：
美国
起止时间：
2018-01-17 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10008136
关键词：
Acute Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Apoptosis Attenuated Bacteria Bacterial Antibiotic Resistance Bacterial Infections Benchmarking Blood CXCL1 gene Centers for Disease Control and Prevention (U.S.)Cessation of life Chemotherapy-Oncologic Procedure Clinical Communicable Diseases Consumption Cytoplasmic Granules Data Development Disease Dose Economic Burden Elderly Engineering Enzymes Event Frequencies Histopathology Homeostasis Immune response Immunity Immunocompromised Host Individual Infection Inflammation Invaded Investments Lymphatic Mediating Microbe Microbial Antibiotic Resistance Modeling Modern Medicine Molecular Morbidity - disease rate Mus Neutrophil Infiltration Operative Surgical Procedures Pathogenicity Peptides Phase Phenotype Play Population Process Regulation Research Resolution Role Runaway Salmonella Salmonella enterica Salmonella typhimurium Sepsis Structure Superoxides Testing Therapeutic Time Tissues Transplantation Treatment Efficacy Variant Vulnerable Populations cell injury chemokine combat cost cytokine design dimer dosage drug development drug discovery drug resistant pathogen emerging antibiotic resistance insight interest lipid mediator macrophage microbial monocyte monomer mortality mouse model neutrophil novel novel strategies novel therapeutics prevent prophylactic public health relevance recruit restoration synergism therapeutic evaluation trafficking

项目摘要

Many bacterial infections, especially those that are resistant to antibiotics, in the young, elderly, and immunocompromised, are characterized by runaway inflammation and sepsis. A hallmark of acute microbial infections is the chemokine-mediated recruitment of neutrophils to the infected tissue. Activated neutrophils release granule enzymes/peptides and superoxide for microbial killing. These processes must be highly regulated, as too many neutrophils will result in collateral tissue damage and disease. Such regulation, under conditions of high bacterial loads and/or when antibiotics are ineffective, is detrimental with infection winning the battle. We propose augmenting the host immune response as a viable strategy for containing bacterial infection. We have discovered that the ability of chemokines to exist as monomers and dimers plays an important role in regulating neutrophil function. We will test the hypothesis that exogenously administered chemokine variants, by promoting neutrophil function, enable successful resolution of inflammation and restoration of tissue homeostasis. In Aim 1, we will test the therapeutic efficacy of a chemokine dimer by optimizing dosage, timing and frequency of administration after infecting mice with a lethal Salmonella Typhimurium (S. Typhimurium) dose in a septicemic model. In Aim 2, we will determine how successful resolution is restored in chemokine treated mice by characterizing neutrophil and macrophage phenotypes including neutrophil killing activity, and cytokine/chemokine and lipid mediators that serve as benchmarks along the initiation to resolution phase. Our hypothesis, that the host immune response can be skewed for successful resolution of inflammation using engineered chemokines, is novel. Bacterial diseases cause significant morbidity, mortality, and economic burden, and are quickly developing antibiotic resistance. Our study will identify the molecular basis of cellular injury and disease exacerbation, enabling discovery and development of more effective therapeutics to treat infectious diseases, especially those that are associated with multi- antibiotic-resistant pathogens.

许多细菌感染，特别是那些对抗生素有抗药性的，发生在年轻人、老年人和老年人身上