BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10582394
• 负责人: Thomas S Griffith
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582394
• 关键词: Acute; Address; Adult; Age; American; Award; B-Lymphocytes; Biology; Biomedical Research; Birth; CD4 Positive T Lymphocytes; Cause of Death; Cell Compartmentation; Cells; Cellular Immunity; Cessation of life; Chronic; Classification; Clinical; Clinical Research; Clinical Treatment; Collaborations; Critical Illness; Data; Development; Diagnosis; Dissection; Doctor of Philosophy; Event; Expenditure; Exposure to; Functional disorder; Funding; Goals; Grant; Growth; Health; Healthcare; Healthcare Systems; Heterogeneity; Hospital Mortality; Hospitalization; Hospitals; Housing; Human; Human Biology; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Adjuvants; Immunosuppression; Impairment; Incidence; Infection; Innate Immune Response; Inpatients; Institution; Intervention; Investigation; Iowa; Knowledge; Laboratories; Laboratory mice; Medical; Minnesota; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Paper; Patients; Persons; Physiological; Population; Positioning Attribute; Pre-Clinical Model; Productivity; Public Health; Publications; Publishing; Reporting; Reproducibility; Research; Research Activity; Research Personnel; Resources; Sampling; Scientist; Sepsis; Shapes; Specialist; Survivors; T-Lymphocyte; Testing; Training; Treatment Efficacy; United States National Institutes of Health; Universities; Urology; Vaccination; Veterans; Vulnerable Populations; Work; aging population; career; clinical translation; clinically relevant; clinically significant; commensal microbes; comorbidity; cytokine; cytokine release syndrome; emerging pathogen; expectation; experience; fitness; germ free condition; gut microbiota; health science research; hospital readmission; improved; indexing; insight; memory CD4 T lymphocyte; microbial; mortality; mouse model; neonate; novel; pathogen; pathogen exposure; pathogenic microbe; pre-clinical; pre-clinical research; preclinical efficacy; preclinical study; professor; readmission rates; recidivism; recurrent infection; response; secondary infection; septic; septic patients; success; Acute; Address; Adult; Age; American; Award; B-Lymphocytes; Biology; Biomedical Research; Birth; CD4 Positive T Lymphocytes; Cause of Death; Cell Compartmentation; Cells; Cellular Immunity; Cessation of life; Chronic; Classification; Clinical; Clinical Research; Clinical Treatment; Collaborations; Critical Illness; Data; Development; Diagnosis; Dissection; Doctor of Philosophy; Event; Expenditure; Exposure to; Functional disorder; Funding; Goals; Grant; Growth; Health; Healthcare; Healthcare Systems; Heterogeneity; Hospital Mortality; Hospitalization; Hospitals; Housing; Human; Human Biology; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Adjuvants; Immunosuppression; Impairment; Incidence; Infection; Innate Immune Response; Inpatients; Institution; Intervention; Investigation; Iowa; Knowledge; Laboratories; Laboratory mice; Medical; Minnesota; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Paper; Patients; Persons; Physiological; Population; Positioning Attribute; Pre-Clinical Model; Productivity; Public Health; Publications; Publishing; Reporting; Reproducibility; Research; Research Activity; Research Personnel; Resources; Sampling; Scientist; Sepsis; Shapes; Specialist; Survivors; T-Lymphocyte; Testing; Training; Treatment Efficacy; United States National Institutes of Health; Universities; Urology; Vaccination; Veterans; Vulnerable Populations; Work; aging population; career; clinical translation; clinically relevant; clinically significant; commensal microbes; comorbidity; cytokine; cytokine release syndrome; emerging pathogen; expectation; experience; fitness; germ free condition; gut microbiota; health science research; hospital readmission; improved; indexing; insight; memory CD4 T lymphocyte; microbial; mortality; mouse model; neonate; novel; pathogen; pathogen exposure; pathogenic microbe; pre-clinical; pre-clinical research; preclinical efficacy; preclinical study; professor; readmission rates; recidivism; recurrent infection; response; secondary infection; septic; septic patients; success

Sepsis remains the leading cause of hospital mortality today. Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality from sepsis has significantly declined over the past decade. This decline in mortality is due in large part to earlier recognition and better compliance with best practices in early sepsis management. Despite decreased in-hospital mortality, a large fraction (up to 50% in some studies) of sepsis survivors never fully recover and develop chronic critical illness – characterized by persistent immune suppression, recurrent infections, sepsis recidivism, and poor long-term outcomes. The applicant of this BLRD Merit Review Research Career Scientist (RCS) Award is Thomas S. Griffith, Ph.D., a Research Health Science Specialist at the Minneapolis VA Health Care System (MVAHCS) currently supported by two VA Merit Awards (I01 BX001324-10 and I01 BX001324-01). Dr. Griffith is also a Professor (with tenure) in the Department of Urology at the University of Minnesota, serving as PI on two NIH grants (1R35 GM140881-01 and 1R21 AI154527-01) and co-investigator on a third NIH grant (1R01 CA260825-01). Over the past 12 years, the applicant’s laboratory has been investigating sepsis-induced immune suppression using a combination of multiple preclinical models and human samples. Current preclinical research activities in the applicant’s laboratory leverage a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections to train the immune system for robust responses to new pathogens. Environmental pathogen exposure is one important difference between basic human and laboratory mouse biology that must be considered when using mice to evaluate immune system fitness. Humans are naturally exposed to both commensal and pathogenic microbes daily from birth, and the immune system of adult humans has been trained and shaped by each infection and vaccination experienced. While specific pathogen-free (SPF) housing of laboratory mice has been instrumental in increasing experimental reproducibility, it has simultaneously further distanced the mouse as a model from humans largely because SPF mice live their lives with limited microbial exposure. Thus, the over-arching goal of the research performed in Dr. Griffith’s laboratory is to study how changing the “starting point” of the immune system (i.e., mature, adult-like immune system of ‘dirty’ mice that have experienced physiological microbial exposure vs. naïve, neonate-like immune system of SPF mice) influences the magnitude of the acute innate immune response to a septic event. Moreover, the work being done may also help to address the important fact that there is a lack of successful treatments for humans with sepsis. Over 100 agents (many targeting cytokines) with preclinical efficacy in mouse models of sepsis have been unsuccessful in humans, making it tempting to speculate the exclusive use of SPF mice in previous preclinical studies may have underestimated the magnitude of the sepsis-induced cytokine storm and/or pathophysiology. It is expected that comparing the extent of immune dysfunction during sepsis in microbially-experienced ‘dirty’ mice to human samples will help to validate the clinical relevance of this novel mouse model that mimics this critical aspect of human biology – exposure to multiple infectious pathogens that generates an experienced immune system – to serve as an important addition to the preclinical toolbox for studying sepsis. An key component of the work performed is the expectation of making the research discoveries available to other researchers and clinicians to help inform the development and testing of new treatment options to improve the health needs of our nation’s Veterans who have experienced a septic event. It is the applicant’s goal to use this RCS award to help him put the applicant’s laboratory in the position to continue this trajectory towards clinical translation of important insights in sepsis pathophysiology gained from basic biomedical research.

败血症仍然是当今医院死亡率的主要原因。尽管由于老化而发病率增加 合并症较高的人口，败血症的院内死亡率在过去显着下降 十年。死亡率下降在很大程度上是由于早期认可和更好地遵守最佳 败血症早期管理的实践。尽管院内死亡率降低，但大部分很大（最多50％ 一些研究）败血症存活永远不会完全康复和发展慢性危害疾病 - 以 持续的免疫抑制，反复感染，败血症累犯和长期结局不佳。 这一值得评论研究职业科学家（RCS）奖的申请人是Thomas S. Griffith博士， 明尼阿波利斯VA医疗保健系统（MVAHCS）的研究健康科学专家 由两个VA优异奖（I01 BX001324-10和I01 BX001324-01）的支持。格里菲斯博士也是教授 （任期）在明尼苏达大学的泌尿外科系，在两项NIH赠款中担任PI （1R35 GM140881-01和1R21 AI154527-01）和第三个NIH赠款（1R01 CA260825-01）上的共同研究器。 在过去的12年中，申请人的实验室一直在研究败血症诱导的免疫抑制 结合了多个临床前模型和人类样品。当前的临床前研究活动 在申请人的实验室中，一种新型的小鼠模型，模仿人类生物学的关键方面 - 暴露于多种正在进行的和解决的感染，以训练免疫系统，以对新的反应进行强有力的反应 病原体。环境病原体暴露是基本人与 使用小鼠评估免疫系统健身时必须考虑的实验室小鼠生物学。 人类每天从出生开始就自然暴露于共生和致病性微生物，免疫 成年人的系统已受到每种感染和疫苗接种的训练和塑造。尽管 实验室小鼠的特异性无病原体（SPF）壳体对增加实验性发挥了作用 可重复性，它同时使小鼠成为一个模型，主要是因为 SPF小鼠在微生物暴露量有限的情况下过着生活。 这是格里菲斯博士实验室中进行的研究的整个目标是研究如何改变 免疫系统的“起点”（即具有成熟的，成年的成人免疫系统的'脏'小鼠 经验丰富的物理微生物暴露与幼稚的，新生儿样的SPF小鼠的免疫学系统）影响 急性先天免疫反应对化粪池事件的大小。而且，完成的工作可能 还有助于解决一个重要的事实，即缺乏对败血症的人类缺乏成功的治疗方法。 在败血症小鼠模型中，超过100多种具有临床前效率的代理（许多靶向细胞因子）已经 在人类中失败，使得在以前的临床前推测SPF小鼠的独家使用很容易 研究可能低估了败血症诱导的细胞因子风暴和/或病理生理学的大小。 可以预期，在微生物经验的“脏”中比较败血症期间免疫功能障碍的程度 对人类样品的小鼠将有助于验证这种模拟这一新型小鼠模型的临床相关性 人类生物学的关键方面 - 暴露于产生经验的多种感染性病原体 免疫系统 - 作为用于研究败血症的临床前工具箱的重要补充。钥匙 执行的工作的组成部分是期望使其他研究发现可用于其他 研究人员和临床医生有助于告知新治疗方案的开发和测试，以改善 经历了化粪池活动的国家退伍军人的健康需求。使用此目的是申请人的目标 RCS奖是为了帮助他将申请人的实验室置于继续临床轨迹的位置 从基本生物医学研究中获得的脓毒症病理生理学中重要见解的翻译。