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（由申请人提供）：这个指导临床科学家职业发展奖（K 08）将为我不断发展成为一名独立研究人员提供培训和支持。我是罗得岛医院的创伤/重症监护外科医生，被任命为布朗大学外科助理教授。我的职业道路一直旨在照顾危重病和创伤性损伤的外科病人，重点是败血症。这是证明了培训在一个繁忙的忙碌1级创伤中心的指导下，著名的专家在外科感染。这段时间允许形成健全的研究原则，并为未来的努力提供了一个重点。其次是创伤和外科重症监护研究金，以及对重症疾病的深入研究，强调败血症和终末器官衰竭。在罗得岛医院/布朗大学任职后，我听从了建议，在最初的几年里建立了自己的临床地位，同时建立了成功的外科医生科学家职业生涯所需的科学框架。这包括与我的主要导师Alfred Ayala博士密切合作，Alfred Ayala博士是一位资金充足，国际公认的败血症研究者，以及我的共同导师Laurent Brossay博士，国际公认的iNKT细胞研究者。这最终被授予休克协会的初级教师补助金，以及SURDNA基金会的补助金，以评估重症和受伤老年患者的免疫功能障碍。自首次提交以来，Laurnt Brossay博士已成为并将继续担任共同主要导师。我继续研究iNKT细胞和巨噬细胞之间的相互作用，通过HMGB-1推进潜在的联系。我继续发表iNKT/败血症/重症监护。我在罗得岛医院的外科研究部工作。我继续受益于一个富含炎症、感染和免疫力的环境。我曾在布朗大学病理学系和分子微生物学与免疫学系工作。罗得岛医院和布朗校区都有充足的资源（人员和设备），以确保拟议项目的成功。罗得岛医院和布朗大学都被指定为生物医学研究卓越中心（COBRE）。我受益于持续的保护时间的研究，我保证至少有75%的保护时间为这个建议。我的个人发展计划是全面的，有短期和长期的目标。这还包括一个研究委员会，由具有教学和指导研究生和研究生以及初级教师的跟踪记录的高级教师组成。我的研究委员会将继续包括一位资金充足的外科医生科学家，他将继续作为一名独立资助的外科医生科学家为我的外科生涯提供建议和指导，并以指导外科研究为长期目标。我将继续参加布朗大学和罗得岛医院提供的课程，因为它们涉及先天免疫学，统计学，研究设计，负责任的研究行为，以及国家研讨会。我的近期职业目标是建立并完成一个多年的研究项目，调查脓毒症后的免疫功能障碍，建立作为外科医生科学家调查员的独立性。长期的科学目标将是将这些发现转化为床边，从而对重症脓毒症患者的护理产生积极影响。为此，我已经证明了在小鼠模型中观察到的淋巴细胞/iNKT相关免疫功能障碍的几个重要方面也存在于重症脓毒症患者中。我已经证明了小鼠和人类在脓毒症、危重病和损伤后淋巴细胞和恒定自然杀伤T细胞（iNKT细胞）特征方面的相似性。这包括几种关键的共抑制受体（如PD-1、BTLA），以及HMGB-1的潜在作用。这一提议继续扩大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随后变化的理解。迄今为止，我的初步数据已经证明，脓毒症后，活化的iNKT细胞似乎迁移到腹腔，改变巨噬细胞吞噬能力和表型，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iNKT细胞与重症脓毒症ICU患者死亡率之间的关键关联。为了扩展这些初步发现并提供更多的机制基础，所提出的实验将测试脓毒症激活、改变和动员不变的NKT细胞以及这些脓毒症iNKT细胞调节巨噬细胞对脓毒性休克的反应的假设。该提案的结构有三个具体目标：1）确定脓毒症是否诱导iNKT细胞表型、功能和无反应性程度的变化：2）使用iNKT细胞敲除小鼠，我们将定义iNKT细胞在改变脓毒症腹膜巨噬细胞功能中的作用：3）为了扩大桥接机制，如DAMP、Alarmin、PAMP等，其介导细胞：由于iNKT-细胞和巨噬细胞之间存在细胞相互作用，我们将评估HMBG-1作为常见的外源性介质（DAMP）在调节脓毒症中所见的iNKT-细胞：巨噬细胞相互作用中的特定作用。预计这项工作的结果将有可能确定未来脓毒症策略的治疗靶点。我相信，我是一个理想的候选人，这个指导职业发展奖（K 08）在我的道路上独立作为一个外科医生科学家。