MOLECULAR PATHOGENESIS OF GUT INJURY IN MOF

MOF 肠道损伤的分子发病机制

• 批准号: 6813354
• 负责人: BRUCE C. KONE
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6813354
• 关键词: biological signal transduction; disease /disorder model; gastrointestinal disorder; gastrointestinal disorder chemotherapy; gastrointestinal epithelium; genetic regulation; hormone regulation /control mechanism; immunoregulation; ischemia; laboratory rat; melanocyte stimulating hormone; molecular pathology; multiple organ failure; nonhuman therapy evaluation; phosphorylation; posttranslational modifications; protein structure function; reperfusion; transcription factor; trauma

Acute ischemia and reperfusion (I/R) is a common consequence of post-traumatic shock and resuscitation characterized by local and systemic derangements that may result in multiple organ failure (MOF). To date, there remains limited information about the injurious and protective mechanisms endogenous to the gut following I/R, and there have been no specific therapies for this disorder. Work to date in our laboratory has identified differential phosphorylation of IKBc?as a key signaling component leading to gut injury following mesenteric I/R. In addition, we have demonstrated a remarkable effect of alpha-melanocyte stimulating hormone (alpha-MSH), an endogenous anti-inflammatory peptide known to abrogate lung and liver injury in MOF, to protect the gut from I/R injury. Similarly, we determined that topical hypothermia applied to the gut during ischemia was also protective against I/R injury. Finally, we developed a model of ischernic preconditioning of the gut in rats that provides opportunities to explore the identities and roles of endogenous protective and deleterious genes. The current proposal builds on these findings and the overall themes of the Center to examine specific molecular programs in the gut that either promote or defend against injury and dysfunction, and to determine whether these pathways can be modulated to therapeutic benefit. Aim 1 will seek to establish the optimal therapeutic use of alpha-MSH and related analogues in a rat model of gut I/R, with an eye toward translating this therapy to trauma victims in the future. Aim 2 will examine the specific alpha-MSH-inhibitable signaling pathways that result in tyrosine phosphorylation of IkappaBalpha, NF-kappaB activation, and cell injury in gut I/R and in cultured intestinal epithelial cells subjected to hypoxia-reoxygenation. Using gene expression profiling, Aim 3 will pursue the identities of novel genes that are activated or repressed during gut I/R and those that afford endogenous protection during ischemic preconditioning of the gut. These studies involve interactions with all of the projects and cores of the Center, and should provide important insights into the mechanisms by which signals initiated from I/R trigger changes in expression of protective genes in the gut, and, more broadly, the pathobiology of MOF. It is anticipated that these studies will facilitate the rational development of novel therapies that selectively and beneficially regulate the expression of genes promoting this syndrome.

急性缺血再灌注（I/R）是创伤后休克和复苏的常见后果，其特征是局部和全身紊乱，可能导致多器官衰竭（MOF）。迄今为止，关于I/R后肠道内源性损伤和保护机制的信息仍然有限，并且没有针对这种疾病的特异性治疗方法。迄今为止，我们实验室的工作已经确定了IKBc？作为导致肠系膜I/R后肠道损伤的关键信号成分。此外，我们