Mechanisms of translation arrest following focal brain ischemia.

摘要

The loss of blood flow to the brain is termed ischemia and the subsequent resumption of blood flow is termed reperfusion. Brain ischemia and reperfusion (I/R) occurs primarily following resuscitation from cardiac arrest and stroke and presents one of the most significant clinical challenges. At present, there are no clinically effective pharmacologic interventions to halt brain damage following I/R. The major Aim of this dissertation will be to investigate possible mechanisms involved in neuron death following brain I/R, which may potentially lead to the development of effective therapies.;A second major facet of this dissertation will be to address the issue of stroke and diabetes. It is very well established clinically that stroke outcome in diabetic patients is significantly worse than in non-diabetic patients. Diabetes has negative effects throughout the whole body and multiple different causes have been attributed to worsened stroke outcome. As both diabetes and stroke are stress to cells, I will hypothesize that the worsened damage is due to a cumulative or additive effect of each condition on neuronal stress responses. Neuronal death following brain I/R injury is a result of a variety of damage pathways. The focus of the work here is on a single feature of I/R injury: the persistent inhibition of protein synthesis, or translation arrest (TA), which occurs in neurons in response to I/R injury. TA is of significance because, as I discuss in detail below, it correlates with neuronal death. The purpose of this Dissertation is to investigate mechanisms of TA in the brain following focal ischemia, with and without diabetes. There has been extensive research on persistent TA in global models of brain I/R, whereas research in focal ischemia, as occurs in stroke, has not been as extensive. Therefore, there is a need to further study mechanisms of TA in the focal model. After a thorough literature review, I have found no studies of the possible role of TA in worsened stroke outcome in diabetics, making this line of investigation completely novel.;Below, I will review our current understanding of I/R brain injury and how diabetes worsens outcome. I will discuss clinical outcomes, the major mechanisms, and especially focus on TA following brain I/R. The most current ideas on TA link it to intracellular stress responses and the formation of subcellular particles involved in mRNA metabolism such as stress granules and mRNA granules. My Background discussion will lead to my hypotheses about mechanisms of prolonged TA following focal brain I/R and the possible effect of diabetes on these mechanisms. In subsequent chapters I will present my study designs and results. The Dissertation will close with a chapter discussing the significance of my finding in light of the existent literature and in terms of new ideas about cell injury dynamics that are being developed in our laboratory.