Dendritic Cell Dysfunction in Post-CLP Immunosuppression

CLP 免疫抑制后树突状细胞功能障碍

基本信息

批准号：
7664265
负责人：
ERLE D MURPHEY
金额：
$ 12.16万
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：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664265
关键词：
Adoptive Transfer Advisory Committees Affect Aftercare Aliquot Anesthesiology Attenuated Bacterial Infections Blood Burn injury Cell Culture Techniques Cell Differentiation process Cell physiology Cells Cellular Immunity Coculture Techniques Collaborations Commit Critical Illness Culture Media Data Defense Mechanisms Dendritic Cells Development Flow Cytometry Functional disorder Goals Harvest Heating Helper-Inducer T-Lymphocyte Immune response Immunologics Immunology Immunosuppression Impairment Infection Injury Institutes Interleukin-10 Interleukin-12 Interleukin-4 Journals Knockout Mice Knowledge Ligation Liquid substance Liver Lung Lymphocyte Mentorship Messenger RNA Modeling Molecular Molecular Biology Morbidity - disease rate Mus Natural Killer Cells Organism Patients Pattern Phenotype Physicians Physiological Play Population Predisposing Factor Predisposition Principal Investigator Production Proteins Pseudomonas Puncture procedure Regulation Research Research Design Research Personnel Resistance Resistance to infection Resources Resuscitation Role Sampling Scientist Sepsis Serum Proteins Signal Transduction Source Spleen Splenocyte Suppressor-Effector T-Lymphocytes Syndrome T-Cell Proliferation Techniques Training Trauma Work acquired immunity antimicrobial bacterial resistance base cytokine immunosuppressed improved insight intravenous injection killings mRNA Expression macrophage meetings microbial mortality novel novel therapeutics reconstitution research study response secondary infection skills

项目摘要

DESCRIPTION (provided by applicant): This K08 application is a proposal for the development of the applicant towards scientific independence while performing research to develop novel insights into the pathophysiology of injury-induced immunosuppression and study a novel therapeutic strategy for this syndrome. The applicant will investigate post-injury immunosuppression under the guidance of an advisory committee led by Drs. Edward Sherwood and Frank Schmalstieg. These investigators have each made strong contributions to the fields of sepsis and burn injury, and have committed to providing the applicant with strong mentorship and training in molecular and immunologic experimental techniques. The applicant will also benefit from his unique placement within the Shriners' Burns Institute which provides avenues for collaboration and development of junior investigators through weekly scientific review meetings. Finally, the applicant intends to round out his development with participation in a number of didactic pursuits, including immunology journal clubs and weekly seminars, and post-graduate classes in immunology, flow cytometry, molecular biology. While investigating the innate immune response during an immunosuppressed state, the applicant will acquire new knowledge and skills necessary to develop a strong background in basic and applied immunology. The Dept. of Anesthesiology and the Shriners' Burns Institute at UTMB provide expertise from diverse resources and provide an ideal setting for training scientists. Patient survival after a severe injury or infectious insult has been greatly improved by the capacity of physicians to provide fluid resuscitation and physiological support. However, secondary infection is a major cause of morbidity and mortality in these patients. Post-injury immunosuppression is emerging as a predisposing factor for the development of secondary infection. Our preliminary studies show that dendritic cell and macrophage dysfunction contribute significantly to the state of immunosuppression observed in the critically ill host. The purpose of the proposed research is to further define dendritic cell and macrophage function during the post-injury period and examine the ability of the hemopoietic factor Flt3-L to improve dendritic cell function and resistance to secondary infection. The specific aims include: 1) Investigating the role that altered dendritic cell function plays in diminished bacterial clearance after cecal ligation and puncture; 2) Determining if Flt3-L expansion of dendritic cells results in increased IL-12 and IFNgamma expression and enhanced resistance to infection; and 3) Investigating the role that altered macrophage function plays in diminished bacterial clearance after cecal ligation and puncture with particular emphasis on the study of a subset of macrophages that have been termed 'natural suppressor' cells and have the potential to differentiate into dendritic cells.

描述（由申请人提供）：该K08的应用是申请人发展科学独立性的建议，同时进行研究以发展对损伤诱导的免疫抑制的病理生理学的新见解，并研究了该综合征的新型治疗策略。申请人将在由Drs领导的咨询委员会的指导下调查伤害后的免疫抑制。爱德华·舍伍德（Edward Sherwood）和弗兰克·施马斯蒂（Frank Schmalstieg）。这些研究人员各自为败血症和烧伤损伤领域做出了巨大贡献，并致力于为申请人提供强大的指导和分子和免疫学实验技术的培训。申请人还将受益于他在Shriners'Burns Institute中的独特位置，该研究所通过每周的科学审查会议为协作和开发初级研究人员提供途径。最后，申请人打算通过参加多种教义追求，包括免疫学期刊俱乐部和每周一次的研讨会以及免疫学，流式细胞术，分子生物学的研究生课程。在调查免疫抑制状态下先天免疫反应的同时，申请人将获得开发基本和应用免疫学背景所必需的新知识和技能。 UTMB的麻醉学和Shriners'Burns Institute的部门提供了来自不同资源的专业知识，并为培训科学家提供了理想的环境。严重受伤或感染性损伤后的患者生存已被医生提供液体复苏和生理支持的能力大大提高。但是，继发感染是这些患者发病率和死亡率的主要原因。损伤后免疫抑制正在成为继发感染发展的诱发因素。我们的初步研究表明，树突状细胞和巨噬细胞功能障碍对在批判性宿主中观察到的免疫抑制状态有显着贡献。拟议的研究的目的是在伤害后期进一步定义树突状细胞和巨噬细胞功能，并检查血压因子FLT3-L的能力提高树突状细胞功能和对继发感染的抗性。具体目的包括：1）研究改变树突状细胞功能在盲结扎和穿刺后细菌清除率降低的作用； 2）确定树突状细胞的FLT3-L膨胀是否导致IL-12和IFNGAMMA表达增加并增强对感染的抗性； 3）研究改变巨噬细胞功能在盲肠结扎和穿刺后降低的细菌清除率中发挥作用的作用，特别强调研究巨噬细胞的一部分，这些巨噬细胞被称为“天然抑制剂”细胞，并有可能区分为树枝状细胞。