BLRD Research Career Scientist Award Application

脓毒症仍然是当今医院死亡的主要原因。尽管随着年龄的增长， 在合并症较多的人群中，脓毒症的住院死亡率在过去显著下降 十年死亡率的下降在很大程度上是由于更早地认识到这一点， 早期脓毒症管理的实践。尽管住院死亡率下降，但很大一部分（在2010年高达50%） 败血症幸存者从未完全康复并发展为慢性危重病-其特征在于 持续性免疫抑制、复发性感染、败血症复发和不良长期结局。 本BLRD Merit Review Research Career Scientist（RCS）Award的申请人是托马斯S。格里菲斯博士， 明尼阿波利斯VA医疗保健系统（MVAHCS）的研究健康科学专家，目前 由两个VA优异奖（I01 BX 001324 - 10和I01 BX 001324 - 01）支持。格里菲斯博士也是一名教授 (with在明尼苏达大学泌尿系担任两项NIH资助的PI (1R35 GM140881 - 01和1R21 AI154527 - 01）和第三次NIH资助的共同研究者（1R01 CA260825 - 01）。 在过去的12年里，申请人的实验室一直在研究脓毒症引起的免疫抑制 使用多个临床前模型和人体样本的组合。当前临床前研究活动 在申请人的实验室中，利用了一种新型小鼠模型，该模型模拟了人类生物学的一个关键方面- 暴露于多种正在进行和已解决的感染，以训练免疫系统对新的 病原体环境病原体暴露是基本人类和 在使用小鼠评估免疫系统适应性时必须考虑的实验室小鼠生物学。 人类从出生起就每天自然地暴露于肠道和病原微生物， 成年人的免疫系统已经通过每一次感染和疫苗接种经历得到训练和塑造。而 无特定病原体（SPF）的实验室小鼠饲养有助于增加实验 可重复性，它同时进一步将小鼠作为人类的模型，主要是因为 SPF小鼠在有限的微生物暴露下生活。 因此，格里菲斯博士实验室进行的研究的首要目标是研究如何改变 免疫系统的"起始点"（即，“脏”老鼠的成熟的、成人样的免疫系统， 经历过生理微生物暴露与SPF小鼠的幼稚、类似免疫系统）的影响 对脓毒症事件的急性先天免疫反应的程度。此外，正在进行的工作可能 也有助于解决一个重要的事实，即缺乏成功的治疗人类脓毒症。 超过100种在败血症小鼠模型中具有临床前疗效的药物（许多靶向细胞因子）已被研究。 在人类中不成功，这使得人们很容易推测SPF小鼠在先前的临床前研究中的独家使用。 研究可能低估了脓毒症诱导的细胞因子风暴和/或病理生理学的程度。 预计比较在败血症期间免疫功能障碍的程度，在微生物经历的"脏" 小鼠与人类样本的比较将有助于验证这种新型小鼠模型的临床相关性， 人类生物学的一个重要方面-暴露于多种传染性病原体， 免疫系统-作为研究败血症的临床前工具箱的重要补充。an密钥 所做工作的一部分是期望将研究发现提供给其他人 研究人员和临床医生，以帮助通知新的治疗方案的开发和测试，以改善 我们国家的退伍军人谁经历了败血症事件的健康需求。申请人的目标是使用此 RCS奖，以帮助他把申请人的实验室的位置，继续这一轨道走向临床 从基础生物医学研究中获得的脓毒症病理生理学的重要见解的翻译。

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.