Gut Circadian Clock and Melatonin Dynamics Following Major Thermal Injury

严重热损伤后的肠道昼夜节律时钟和褪黑激素动态

• 批准号: 8610325
• 负责人: WALID M AL GHOUL
• 金额: $ 10.88万
• 依托单位: CHICAGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-22 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610325
• 关键词: Academic Medical Centers; Address; Affect; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Bacteria; Bacterial Toxins; Burn Trauma; Burn injury; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chicago; Chronic; Circadian Rhythms; Collaborations; Critical Care; Data; Development; Disease; Distal part of ileum; Educational process of instructing; Environment; Enzymes; Evaluation; Functional disorder; Funding; Future; Gastroenterology; Goals; Grant; Health Services Research; Human; Immunohistochemistry; In Situ; In Situ Hybridization; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Institution; Intensive Care Units; Intestines; Jet Lag Syndrome; Light; Link; Literature; Lymph; Mainstreaming; Measurement; Medical; Melatonin; Mentors; Metabolic; Minority; Modeling; Molecular; Mucous Membrane; Multiple Organ Failure; Paper; Pathogenesis; Patients; Performance; Peripheral; Pharmaceutical Preparations; Principal Investigator; Production; Publications; Publishing; Regimen; Reporting; Research; Scholarship; Sepsis; Sepsis Syndrome; Septicemia; Site; Sleep; Sleep Deprivation; Source; Testing; Time; Tissues; United States; Universities; Vital Statistics; Work; abstracting; base; career; circadian pacemaker; combat; cost; falls; gastrointestinal epithelium; heat injury; improved; innovation; molecular dynamics; molecular marker; novel; spatiotemporal; tool

DESCRIPTION (provided by applicant): Following Major Thermal Injury Abstract Sepsis is a serious uncontrolled systemic inflammatory response associated with or triggered by infection and often leading to multiple organ failure and death. It has been reported to be the 10th leading cause of death in the US and the main cause of death among major burn and trauma patients and in non-coronary intensive care units. Numerical estimates of sepsis cost range from 33,865 septicemia-related deaths in the year 2002 in the United States alone (National Vital Statistics Reports, 2005) or 18 million cases worldwide at a monitory cost of $17 billion/year as an ICU sepsis patient costs six times as much to treat as a non-sepsis patient (The Surviving Sepsis Campaign, Critical Care 7(1), 2003). The central hypothesis is that gut barrier cellular and molecular mechanisms relevant to postburn intestinal leakiness and sepsis pathogenesis include converging, differential changes in gut mucosa barrier milieu with spatiotemporally-intersecting molecular circadian clock and de novo gut melatonin production dynamics on days 1, 3 and 7 following major thermal injury. This hypothesis is the most logical expansion of the principal investigator's recently published paper on postburn gut melatonin sources and targets (Int J Biol Sci, 2010). It also addresses common grounds between my melatonin work and recent circadian research that he was engaged in developing during his sabbatical at Rush University Medical Center (Fall 2009) where Drs. Keshavarzian and Turek groups (Rush and Northwestern Universities) provided strong evidence for a link between circadian molecular clock machinery and inflammation-related gut barrier pathophysiology. His melatonin data suggests endogenous pathophysiologic melatonin changes being a key determinant of gut background oxidative state thus paving the way for innovative synergistic anti-inflammatory treatments with exogenous melatonin and other drugs. Here, he seeks to examine the spatiotemporal intersection of gut melatonin and circadian clock changes converging at the level of the gut barrier in an established animal model of major burn injury. The strength of his approach is in having identified the dynamic early major postburn gut barrier microenvironment as a site where three illusive tissue injury culprits, namely, intestinal sepsis pathogenesis, peripheral gut molecular circadian clock dysregulation and extra pineal melatonin abnormalities are spatiotemporally juxtaposed and henceforth could be captured. The following specific aims are proposed for testing the central hypothesis: (1) To characterize in situ spatiotemporal changes in gut melatonin sources before and after major thermal injury, (2) To characterize in situ spatiotemporal changes in gut circadian clock molecular markers with and without major thermal injury, and (3) To determine the effect of environmental circadian disruption on gut melatonin and inflammation in the presence and absence of major thermal injury. An essential fourth final aim is: (4) To provide professional development and mentoring for the principal investigator in order to support his professional advancement and improve his ability to successfully tackle the proposed scientific aims. The author's mentoring proposal is to partner with a very active and well- funded as well as well-published research group in the area of gut inflammation and gut barrier function at Rush University Medical Center's Department of Gastroenterology. The mentoring plan is very suitable in light of the strength of the host lab and their excellent recent publications linking gut barrier abnormalities to inflammation as well as circadian clock and melatonin, albeit in IBD and alcohol models. As such, funding of this research will significantly enhance the PI's ability to remain active in his field of research and strengthen his collaboration and importantly his academic evaluation portfolio, because professional advancement at CSU is based on performance in the areas of teaching, service and research/scholarship. The publications due to this grant funding will also enhance the PI's scientific reputation and increase his ability to attract future mainstream grant funding such as SC1 and R01.

描述（由申请人提供）：严重热损伤后摘要脓毒症是一种与感染相关或由感染引发的严重不受控制的全身炎症反应，通常导致多器官衰竭和死亡。据报道，它是美国第十大死因，也是严重烧伤和创伤患者以及非冠状动脉重症监护病房的主要原因。对脓毒症成本的估计范围包括 2002 年仅在美国就有 33,865 例与脓毒症相关的死亡（国家生命统计报告，2005 年）或全世界有 1800 万例病例，每年监测费用为 170 亿美元，因为 ICU 脓毒症患者的费用为 6 美元治疗量是非脓毒症患者的两倍（拯救脓毒症运动，重症监护 7(1)，2003）。 核心假设是，与烧伤后肠渗漏和脓毒症发病机制相关的肠道屏障细胞和分子机制包括肠道粘膜屏障环境与时空交叉的分子生物钟和第1、3和7天肠道褪黑素从头产生动态的聚合、差异变化。严重热损伤后。这一假设是主要研究者最近发表的关于烧伤后肠道褪黑激素来源和目标的论文（Int J Biol Sci，2010）的最合乎逻辑的扩展。它还讨论了我的褪黑激素工作和他最近在拉什大学医学中心（2009 年秋季）休假期间从事的昼夜节律研究之间的共同点，博士们在那里进行了研究。 Keshavarzian 和 Turek 小组（拉什大学和西北大学）为昼夜节律分子钟机制与炎症相关的肠道屏障病理生理学之间的联系提供了强有力的证据。他的褪黑激素数据表明，内源性病理生理学褪黑激素变化是肠道背景氧化状态的关键决定因素，从而为外源性褪黑激素和其他药物的创新协同抗炎治疗铺平了道路。在这里，他试图在已建立的严重烧伤动物模型中检查肠道褪黑激素和生物钟变化在肠道屏障水平上的时空交叉点。他的方法的优势在于确定了动态的早期主要烧伤后肠道屏障微环境是三个虚幻组织损伤罪魁祸首的部位，即肠脓毒症发病机制、外周肠道分子生物钟失调和松果体褪黑激素异常在时空上并置，因此可能被俘虏。 提出以下具体目标来检验中心假设：（1）表征重大热损伤前后肠道褪黑激素来源的原位时空变化，（2）表征有或没有热损伤时肠道生物钟分子标记的原位时空变化(3) 确定在存在和不存在严重热损伤的情况下环境昼夜节律紊乱对肠道褪黑激素和炎症的影响。 第四个重要的最终目标是：（4）为主要研究者提供专业发展和指导，以支持他的专业进步并提高他成功实现所提出的科学目标的能力。作者的指导建议是与拉什大学医学中心胃肠病学系的肠道炎症和肠道屏障功能领域非常活跃、资金充足且发表成果丰富的研究小组合作。鉴于宿主实验室的实力及其最近发表的优秀出版物，该指导计划非常合适，该出版物将肠道屏障异常与炎症以及生物钟和褪黑激素联系起来，尽管是在 IBD 和酒精模型中。因此，这项研究的资助将显着增强 PI 在其研究领域保持活跃的能力，加强他的合作，更重要的是加强他的学术评估组合，因为科罗拉多州立大学的专业进步取决于教学、服务和研究领域的表现/奖学金。这笔赠款资助的出版物还将提高 PI 的科学声誉，并增强他吸引未来主流赠款资助（例如 SC1 和 R01）的能力。