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: 8432449
• 负责人: WALID M AL GHOUL
• 金额: $ 10.49万
• 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/8432449
• 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）：在重大热损伤之后，抽象败血症是一种严重的不受控制的全身性炎症反应，与感染相关或触发，通常导致多器官衰竭和死亡。据报道，这是美国的第十大死亡原因，也是主要烧伤和创伤患者以及非冠军重症监护病房中死亡的主要原因。败血症成本的数值估计值范围从2002年的33,865例与败血症相关的死亡（2005年国家生命统计报告，2005年）或1800万例病例，以170亿美元的成本为ICU Seppsis患者，其成本为170亿美元。 中心假设是，与后胸腔肠道泄漏和败血症发病机理相关的肠道屏障细胞和分子机制包括肠道粘膜屏障环境的差异，差异变化，并在第1天，第1天，第1天和第7天对Novo gut gut Melatin的生产动力学以及de novo gut melatin tynamics进行时空相差。该假设是主要研究者最近发表的有关燃烧后肠道褪黑激素来源和靶标的最合乎逻辑的扩展（Int J Biol Sci，2010年）。它还解决了我在拉什大学医学中心休假期间（2009年秋季）在他的休假期间从事发展的昼夜节律研究之间的共同基础。 Keshavarzian和Turek组（Rush and Northwestern Universities）为昼夜节律分子时钟机械与与炎症相关的肠道屏障病理生理学之间有联系提供了有力的证据。他的褪黑激素数据表明，内源性病理生理学的褪黑激素变化是肠道背景氧化态的关键决定因素，因此为使用外源褪黑激素和其他药物铺平了创新的协同抗炎治疗的道路。在这里，他试图检查肠道褪黑激素和昼夜节律时钟变化的时空交集，在肠道屏障水平上融合的既有重大烧伤损伤模型。 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. 提出了以下特定目的测试中心假设：（1）在重大热损伤之前和之后的肠道褪黑激素源的原位时空变化表征（2），（2）表征原位的时空时空变化，肠圆形昼夜节律钟表分子标志物具有重大热损伤和（3）的效应，并在旋转效应的情况下，并确定旋转的效应，并在旋转效应。没有重大的热损伤。 基本的第四个最终目标是：（4）为主要研究人员提供专业发展和指导，以支持他的专业进步并提高他成功应对拟议的科学目标的能力。作者的指导建议是与Rush大学医学中心胃肠病学系的肠道炎症和肠道障碍功能方面的一个非常活跃和资助的研究小组合作。鉴于主持人实验室的强度以及他们最近的出色出版物将肠道障碍异常与炎症以及昼夜节律时钟和褪黑激素联系起来，尽管在IBD和酒精模型中，但他们最近的出色出版物非常适合。因此，这项研究的资金将显着增强PI在研究领域保持活跃并加强他的协作以及他的学术评估组合的能力，因为CSU的专业进步是基于教学，服务和研究/奖学金领域的表现。由于这笔赠款而引起的出版物还将提高PI的科学声誉，并提高他吸引未来主流赠款资金（例如SC1和R01）的能力。