Dendritic Cell Dysfunction in Post-CLP Immunosuppression

CLP 免疫抑制后树突状细胞功能障碍

• 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
• 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

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)： 这份K08申请是一项建议，旨在使申请者在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针对该综合征的新治疗策略的同时，向科学独立性发展。申请者将在爱德华·舍伍德博士和弗兰克·施马尔斯蒂格博士领导的咨询委员会的指导下调查受伤后的免疫抑制。这些研究人员都在脓毒症和烧伤领域做出了巨大贡献，并致力于为申请者提供强大的分子和免疫学实验技术方面的指导和培训。申请人还将受益于他在施林纳烧伤研究所的独特地位，该研究所通过每周一次的科学审查会议为初级调查人员提供合作和发展的途径。最后，申请者打算通过参加一些教学追求来完善自己的发展，包括免疫学杂志俱乐部和每周研讨会，以及免疫学、流式细胞术、分子生物学的研究生课程。在研究免疫抑制状态下的先天免疫反应时，申请者将获得新的知识和技能，以发展基础和应用免疫学的坚实背景。该部门。麻醉学研究所和UTMB的Shriners‘Burns研究所提供来自各种资源的专业知识，并为培训科学家提供理想的环境。由于医生能够提供液体复苏和生理支持，患者在遭受严重伤害或感染性侮辱后的存活率大大提高。然而，继发感染是这些患者发病和死亡的主要原因。损伤后的免疫抑制正在成为继发感染的诱因。我们的初步研究表明，树突状细胞和巨噬细胞功能障碍对重症宿主的免疫抑制状态有显著影响。本研究的目的是进一步明确损伤后树突状细胞和巨噬细胞的功能，并检测造血因子Flt3-L改善树突状细胞功能和抵抗二次感染的能力。研究的具体目的包括：1)研究树突状细胞功能改变在盲肠结扎和穿孔后细菌清除减少中的作用；2)确定Flt3-L扩增树突状细胞是否会导致IL-12和IFNγ的表达增加，并增强对感染的抵抗力；以及3)研究巨噬细胞功能改变在盲肠结扎和穿孔后细菌清除减少中所起的作用，尤其是重点研究巨噬细胞亚群的研究，这些巨噬细胞被称为“自然抑制细胞”，具有分化为树突状细胞的潜力。