Sepsis Induced Changes in iNKT-Cells and their Effect on Phagocyte Function

脓毒症诱导的 iNKT 细胞变化及其对吞噬细胞功能的影响

• 批准号: 9330170
• 负责人: David Heffernan
• 金额: $ 19.65万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330170
• 关键词: Abdomen; Address; Affect; Alpha Cell; Appointment; Area; Award; Back; Beds; Blood Circulation; CD3 Antigens; CD8B1 gene; Career Choice; Cell Communication; Cell Survival; Cell physiology; Cell surface; Cells; Cellular Structures; Centers of Research Excellence; Characteristics; Clinical; Complex; Critical Care; Critical Illness; Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Development Plans; Doctor of Philosophy; Educational process of instructing; Elderly; Elements; Ensure; Environment; Equipment; Faculty; Failure; Fellowship; Fluid Therapy; Foundations; Funding; Future; Generations; Goals; Grant; Greater sac of peritoneum; HMGB Proteins; Health Care Costs; Hospitals; Human; Human Resources; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunity; Immunology; Infection; Inflammation; Inflammatory Response; Injury; International; K-Series Research Career Programs; KLRB1 gene; Knockout Mice; Knowledge; Kupffer Cells; Ligands; Ligation; Link; Liver; Lymphocyte; Mediating; Mediator of activation protein; Mentors; Microbiology; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Nuclear; Operative Surgical Procedures; Organ failure; Outcome; PDCD1LG1 gene; Patients; Pattern; Peritoneal Macrophages; Phagocytes; Phagocytosis; Phenotype; Play; Positioning Attribute; Production; Protocols documentation; Publishing; Puncture procedure; Records; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Resources; Rhode Island; Role; Scientist; Sepsis; Septic Shock; Shock; Signal Pathway; Societies; Source; Structure; Surgeon; TNFRSF5 gene; Testing; Time; Tissues; Training; Training Support; Translating; Trauma; Universities; Wit; Work; anergy; antimicrobial; antimicrobial drug; blood glucose regulation; career; clinically relevant; cytokine; experimental study; graduate student; immunoregulation; injured; mRNA Expression; macrophage; microbial; migration; mortality; mouse model; professor; public health relevance; receptor; response; responsible research conduct; senior faculty; septic; sound; statistics; success; surgical research; therapeutic target; trauma centers

 DESCRIPTION (provided by applicant): This mentored Clinical Scientist Career Development Award (K08) will provide training and support in my ongoing advancement to becoming an independent researcher. I am a Trauma / Critical Care surgeon at Rhode Island Hospital with an appointment as an Assistant Professor of Surgery at Brown University. My career path has always been aimed at the care of the critically ill and traumatically injured surgical patient, wit an emphasis sepsis. This is evidenced by training at a busy Level 1 trauma center under the tutelage of a renowned expert in surgical infections. This time allowed the formation of sound research principles and offered a focus for future endeavors. This was followed by a fellowship in trauma and surgical critical care and an in-depth study of critical illness emphasizing sepsis and end-organ failure. On taking a position at Rhode Island Hospital / Brown University, I followed advice to establish myself clinically during the first several years while building the scientific frame-work needed for a successful surgeon scientist career. This included working closely with my primary mentor, Alfred Ayala PhD, a well-funded, internationally recognized investigator studying sepsis as well my co-mentor Dr. Laurent Brossay, an internationally recognized investigator in iNKT- cells. This culminated in being award a Junior Faculty Grant from the Shock Society, as well as a grant from the SURDNA foundation to assess immune dysfunction in critically ill and injured geriatric patients. Since the initial submission Dr. Laurnt Brossay has become, and will continue to serve as, a co-primary mentor. I have continued to work on the interaction between iNKT-cells and macrophages advancing the potential link via HMGB-1. I have continued to publish on iNKT/sepsis/critical care. I work within the Division of Surgical Research at Rhode Island Hospital. I continue to benefit, from an environment that is rich in the areas of inflammation, infection and immunity. I have afforded myself of the opportunities of course work within the Department of Pathobiology and Department of Molecular Microbiology and Immunology at Brown University. There are ample resources (personnel and equipment) both at Rhode Island Hospital as well as on the Brown campus to ensure the success of the proposed project. Both Rhode Island Hospital and Brown University have been designated as Centers of Biomedical Research Excellence (COBRE). I have benefited from ongoing protected time for research and I am assured of at least 75% protected time for this proposal. My Individualized Development plan is well-rounded and has short and long term goal. This also includes a research committee consisting of senior faculty with track records of teaching and mentoring graduate and post-graduate students as well as junior faculty. My research committee will continue to include a well-funded surgeon scientist, who continues to advise and guide my surgical career as an independently funded surgeon scientist, with a long term goal of directing surgical research. I will continue to take courses offered at Brown University and Rhode Island Hospital as they relate to innate immunology, statistics, study design, responsible conduct of research, as well as national seminars. My immediate career goal is to establish and complete a multi-year research project investigating immune dysfunction following sepsis, establishing independence as a surgeon scientist investigator. The longer term scientific goal will be to translate these findings back to the bed-side, thereby positively impacting the care of the critically ill septic patient. To this aim, I have already demonstrated that several important aspects of lymphocyte/iNKT related immune dysfunctions noted in a mouse model were also noted to be present in critically ill septic patients. I have demonstrated a similarity across both mice and humans with respect to lymphocyte and invariant Natural Killer T-cell (iNKT-cell) profiles following sepsis, critical illness and injury.This includes several key co-inhibitory receptors (eg PD-1, BTLA), as well as a potential role for HMGB-1. This proposal continues to expand our understanding of how sepsis alters iNKT-cells and how iNKT-cells induce subsequent changes in phagocytes. To date my preliminary data has demonstrated that following sepsis, activated iNKT-cells appear to migrate to the peritoneal cavity, alter macrophage phagocytic capacity and phenotype, and play a role in modulating the HMGB-1 response to sepsis. I have demonstrated a key association between circulating iNKT-cells and mortality in critically ill septic ICU patients. To expand upon these initial findings an offer a more mechanistic basis, the proposed experiments will test the hypothesis that sepsis activates, alters and mobilizes invariant NKT-cells, and that these septic iNKT-cells modulate the macrophage response to septic shock. The proposal is structured in three specific aims: 1) To determine if sepsis induces changes in iNKT-cells phenotype, function and degree of anergy: 2) Using iNKT-cell knock-out mice, we will define the role of iNKT-cells in altering septic peritoneal macrophage function: 3) To extent that a bridging mechanism, such as a DAMP, Alarmin, PAMP, etc, that mediates the cell:cell interaction between iNKT-cells and macrophages exists, we will assess the specific role of HMBG-1 as a common extrinsic mediator (DAMP), in regulating the iNKT-cell:macrophage interaction seen in sepsis. It is anticipated that findings from this work will potentially identify therapeutic targets for future sepsis strategies. I believ that I am an ideal candidate for this mentored career development award (K08) in my road to independence as a surgeon scientist.

 描述（由应用程序提供）：该修订的临床科学家职业发展奖（K08）将在我正在进行的进步中提供培训和支持，成为一名独立的研究人员。我是罗德岛医院的创伤 /重症监护外科医生，被任命为布朗大学外科助理教授。我的职业道路一直是针对重点症的重点症状的重点症状的重症患者。在著名的手术感染专家的指导下，在繁忙的1级创伤中心进行培训可以证明这一点。这次允许形成合理的研究原则，并为将来的努力提供了重点。随后是创伤和手术重症监护的研究金，以及强调败血症和最终器官失败的重症疾病的深入研究。在罗德岛医院 /布朗大学担任职位后，我遵循建议在最初几年的临床上建立自己的建议，同时建立了成功的外科医生职业所需的科学框架工作。这包括与我的主要导师Alfred Ayala PhD紧密合作，Alfred Ayala PhD是一位资金良好的国际认可的研究人员，研究败血症以及我的同事Laurent Brossay博士，Inkt-Cell的国际认可的研究员Laurent Brossay博士。最终获得了冲击协会获得的初级教师赠款，并获得了Surdna基金会的赠款，以评估重病和受伤的老年患者的免疫功能障碍。自从最初提交的Laurnt Brossay博士已成为并将继续作为共同主要的精神。我继续研究通过HMGB-1推进潜在链接的inkt-cell和巨噬细胞之间的相互作用。我继续在inkt/sepsis/重症监护下发布。我在罗德岛医院的外科研究部门工作。我继续从感染，感染和免疫力领域丰富的环境中受益。我为布朗大学病理生物学系和分子微生物学和免疫学系和分子微生物学系的机遇提供了机会。罗德岛医院和布朗校园都有足够的资源（人员和设备），以确保拟议项目的成功。罗德岛医院和布朗大学都被指定为卓越生物医学研究中心（Cobre）。我受益于持续的研究时间，我假设该提案至少有75％的受保护时间。我的个性化开发计划是全面的，并且具有短期和长期目标。这还包括一个由高级教师组成的研究委员会，以及有关教学和心理研究生和研究生以及初级教职员工的记录。我的研究委员会将继续包括一位资金丰富的外科医生科学家，他继续为我作为独立资助的外科医生科学家提供建议和指导我的外科职业，并长期指导手术研究。我将继续参加布朗大学和罗德岛医院提供的课程，因为它们与先天免疫学，统计学，研究设计，负责任的研究行为以及国家 /地区有关。我的直接职业目标是建立和完成一个多年的研究项目，研究败血症后免疫功能障碍，建立独立性，成为外科医生科学家研究员。长期的科学目标将是将这些发现转移回床边，从而积极影响重症患者的护理。为此，我已经证明了小鼠模型中指出的淋巴细胞/INKT相关免疫功能障碍的几个重要方面也存在于重病的化粪池患者中。我已经在淋巴细胞和不变的天然杀手T细胞（Inkt-Cell）剖面，败血症，危重疾病和损伤的情况下都表现出相似之处。这包括几种关键的共抑制受体（例如PD-1，BTLA），以及HMGB-1的潜在作用。该提案继续扩展我们对脓毒症如何改变inkt细胞以及inkt细胞如何诱导吞噬细胞变化的理解。迄今为止，我的初步数据表明，败血症后，激活的inkt细胞似乎迁移到腹膜腔，改变巨噬细胞的吞噬能力和表型，并在调节HMGB-1对脓毒症的反应中发挥作用。我已经证明了循环中的INKT细胞与重症败血症ICU患者的死亡率之间的关键关联。为了扩大这些初始发现的提议，提出的实验将检验败血症激活，改变和动员不变的NKT细胞的假设，并且这些败血性inkt细胞会调节对败血性冲击的巨噬细胞反应。 The proposal is structured in three specific aims: 1) To determine if sepsis induces changes in iNKT-cells phenotype, function and degree of anergy: 2) Using iNKT-cell knock-out mice, we will define the role of iNKT-cells in altering septic peritoneal macrophage function: 3) To extent that a bridging mechanism, such as a DAMP, Alarmin, PAMP, etc, that mediates the cell:cell interaction between存在Inkt-Cells和巨噬细胞，我们将评估HMBG-1作为常见外部介体（湿）的特定作用，在调节ininkt-cell：败血症中看到的巨噬细胞相互作用。可以预料，这项工作的发现将有可能确定未来败血症策略的治疗目标。我相信我是我作为外科医生科学家的独立之路这一Mendored职业发展奖（K08）的理想候选人。