In pursuit of a PICS prognostic: An investigation of the agents activating and perpetuating PICS.

追求 PICS 预后：对激活和维持 PICS 的药物进行调查。

• 批准号: 9268439
• 负责人: David C Holden
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2019-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268439
• 关键词: Acute; Acute-Phase Reaction; Adaptive Immune System; Addendum; Age-Years; Appearance; Bacterial DNA; Bacterial Infections; Blood; Blood Circulation; Blunt Trauma; Caring; Catabolism; Cause of Death; Cessation of life; Chronic; Clinical; Convalescence; Critical Care; Critical Illness; DNA; Development; Diagnosis; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Florida; Funding; Gene Expression; Genetic Transcription; Genomics; Goals; HMGB1 gene; Health; Heat-Shock Proteins 70; Hospitalization; Hospitals; Hour; Immune system; Immunoassay; Immunologics; Immunosuppression; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Investigation; Leukocytes; Lipopolysaccharides; Measures; Medical; Medicine; Mitochondrial DNA; Modernization; Molecular; Multiple Organ Failure; Nuclear; Observational Study; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Persons; Physicians; Plasma; Play; Population; Procedures; Proteins; RNA; Recovery; Recurrence; Refractory; Research; Research Project Grants; Resources; Rhodopsin; Role; S100A8 gene; Sampling; Scientist; Sepsis; Septic Shock; Skilled Nursing Facilities; Stimulus; Supervision; Syndrome; System; Time; Tissues; Training; Trauma; Trauma patient; Traumatic injury; United States; Universities; Wound Healing; base; career; college; cost; cytochrome c oxidase; cytokine; design; evidence based guidelines; human disease; improved; individualized medicine; insight; microbial; mortality; nano-string; nutrition; pathogen; patient population; personalized medicine; prognostic; programs; public health relevance; response; treatment planning

 DESCRIPTION (provided by applicant): The proposed surgery training plan is an integrated critical care doctoral dissertation research project, supervised by Dr. Lyle Moldawer within the Sepsis and Critical Illness Research Center (SCIRC) at the University of Florida, College of Medicine. The program is ideally designed to equip the candidate to attain his career goals of becoming a physician-scientist. Traumatic injuries are presently the leading cause of death for persons less than 45 years of age. Severe sepsis has more than doubled since 2000, and sepsis currently represents the 11th leading cause of death, and the leading diagnosed hospitalization expense. Although trauma and sepsis patients are now increasingly surviving their initial and early insults due to improved acute medical care, unfortunately two year survivability for these patients has remained unchanged. For trauma and sepsis patients, the greatest obstacle to convalescence is now a chronic immunological disequilibrium that we have termed persistent inflammation, immunosuppression and catabolism syndrome (PICS), and the declining clinical course is characterized by a persistent acute-phase response with systemic inflammation, continuous protein catabolism (despite optimal nutrition), poor wound healing, immunosuppression, and recurrent infections. The agents activating and perpetuating PICS are unresolved, and currently there is no established paradigm to discriminate between those patients who will improve clinically within 14 days from those who will progress to PICS. Early, if not immediately after trauma and sepsis onset, pattern recognition receptors (PRRs) that control inflammatory pathways in the innate and adaptive immune system are likely activated by either damage associated molecular patterns [DAMPs: including endogenous mitochondrial DNA and HMGB1] and/or pathogen associated molecular patterns [PAMPs: including bacterial DNA and bacterial lipopolysaccharide] that are released into the circulation during tissue damage and bacterial infection. The objective of this proposal is to develop an early prognostic of trauma and sepsis clinical trajectory, and to gain insight into the agents activating and perpetuating PICS. The overarching hypothesis is that a time-dependent circulatory load of PAMPs and DAMPs dictates whether trauma and sepsis patients recover or enter PICS. Immediately following trauma and sepsis insult, a small amount of blood (less than 10ml) will be drawn from patients in the intensive care unit. Thereafter, for the duration of ICU stay, blood will be periodically drawn to determine the interactions between the immune system and the levels of DAMPs and PAMPs. Leukocyte genomic expression and PAMP levels will be measured with NanoString. DAMP levels will be measured by a combination of qPCR, ELISA, and NanoString. As DAMPs and PAMPs are thought to be associated with an increasing number of diseases, the successful completion of these studies may ultimately contribute to a better understanding of many or most human diseases.

 描述（由申请人提供）：拟议的手术培训计划是一个综合重症监护博士论文研究项目，由佛罗里达大学医学院败血症和危重病研究中心（SCIRC）的Lyle Moldawer博士监督。该计划的理想目的是装备候选人实现他的职业目标，成为一名医生，科学家。目前，创伤是45岁以下者死亡的主要原因。自2000年以来，严重脓毒症增加了一倍多，脓毒症目前是第11大死亡原因，也是诊断住院费用的主要原因。虽然创伤和脓毒症患者由于改善了急性医疗护理而越来越多地在其初始和早期损伤中存活，但不幸的是，这些患者的两年存活率保持不变。对于创伤和脓毒症患者，恢复的最大障碍现在是慢性免疫失衡，我们称之为持续性炎症、免疫抑制和catalysts综合征（PICS），临床病程下降的特征是持续急性期反应伴全身炎症、持续蛋白catalysts（尽管营养最佳）、伤口愈合不良、免疫抑制和复发性感染。激活和维持PICS的药物尚未解决，目前还没有建立的范例来区分那些将在14天内临床改善的患者与那些将进展为PICS的患者。早，如果 在创伤和脓毒症发作后不立即，控制先天性和适应性免疫系统中炎症途径的模式识别受体（PRR）可能被损伤相关分子模式[DAMP：包括内源性线粒体DNA和HMGB 1]和/或病原体相关分子模式[PAMP：包括细菌DNA和细菌脂多糖]，其在组织损伤和细菌感染期间释放到循环中。这项建议的目的是发展创伤的早期预后， 脓毒症的临床轨迹，并获得深入了解的代理激活和永久PICS。总体假设是PAMP和DAMP的时间依赖性循环负荷决定了创伤和脓毒症患者是否恢复或进入PICS。创伤和脓毒症损伤后，将立即从重症监护室的患者身上抽取少量血液（少于10 ml）。此后，在ICU住院期间，将定期抽血 以确定免疫系统与DAMP和PAMP水平之间的相互作用。将使用NanoString测量白细胞基因组表达和PAMP水平。将通过qPCR、ELISA和NanoString的组合测量DAMP水平。由于DAMP和PAMP被认为与越来越多的疾病有关，这些研究的成功完成可能最终有助于更好地了解许多或大多数人类疾病。