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.
Showing the most recent 10 out of 201 publications
