2008 — 2009 |
Zhao, Heng |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Postconditioning Reduces Ischemic Damage After Stroke in Rats
[unreadable] DESCRIPTION (provided by applicant): Ischemic preconditioning has been shown to protect against ischemic damage when given prior to a lethal ischemia, however, its clinical application for stroke patients is possible only when stroke occurrence is predictable. Post-stroke strategies are more feasible for treating patients. One potential post-stroke target is to reduce the damage caused by reperfusion after ischemia. Altering reperfusion in myocardial ischemia has been shown to reduce infract size. Two methods were employed to alter reperfusion: a controlled restoration of blood flow to give a gradual reperfusion; or postconditioning, where reperfusion is interrupted several times. This concept of altered reperfusion has not been tested in the field of stroke research. Thus, we propose to study whether postconditioning or gradual reperfusion reduces ischemic damage after stroke. In our pilot study we found that one model of postconditioning reduced damage in a model of focal ischemia generated by transient bilateral common carotid artery (CCA) occlusion combined with middle cerebral artery (MCA) occlusion. Postconditioning was achieved by a series of short interruptions during reperfusion by releasing and re-occluding the CCAs. We propose to further define the temporal characteristics for postconditioning using this model. In addition, since we previous found that partial reperfusion reduced infarct size compared with complete reperfusion, we will further determine if gradual reperfusion also reduces ischemic damage using a similar focal ischemia model. Finally, we propose to study the potential neuroprotective mechanisms of postconditioning after stroke. In myocardial ischemia, postconditioning was found to be protective by reducing products of reactive oxygen species (ROS) and improving Akt activity. Since both of these also influence neuronal death after stroke and reperfusion, we propose to study the effect of postconditioning on ROS generation and on signals of the Akt survival pathways after stroke. Specific Aim 1. To further define temporal characteristics for postconditioning and explore if gradual reperfusion reduces ischemic infarct. Specific Aim 2. To determine if postconditioning or gradual reperfusion spare neurological function after focal ischemia in rats. Specific Aim 3. To explore the potential neuroprotective mechanisms of postconditioning focusing on Reactive Oxygen Species (ROS) generation and Akt pathway activity. PUBLIC HEALTH RELEVANCE: Postconditioning after stroke reduces ischemic damage, opening up a new avenue for research for stroke treatment. Postconditioning may eventually be clinically applicable for stroke patients. [unreadable] [unreadable] [unreadable]
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0.939 |
2010 — 2019 |
Zhao, Heng |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Protective Mechanisms of Ischemic Postconditioning
DESCRIPTION (provided by applicant): The current lack of effective treatments for acute stroke necessitates exploring innovative concepts that may eventually lead to clinical applications. One such technique is ischemic postconditioning. We have demonstrated that both rapid and delayed ischemic postconditioning reduces infarction in rats. Stroke was induced by a 30 min bCCA occlusion plus permanent distal middle cerebral artery (MCA) occlusion. The bCCA release allows partial reperfusion, which mimics the frequent clinical cases that occur in stroke patients. Rapid postconditioning is applied immediately after reperfusion while delayed postconditioning is conducted 5.5 h after reperfusion. Despite confirmation of the protective effects of postconditioning by several independent research groups, the underlying protective mechanisms are not understood. We have preliminary data showing that rapid postconditioning attenuates reactive oxygen species (ROS) activity, suggesting a correlation between postconditioning and ROS reduction. Whether ROS reduction truly contributes to postconditioning's protective effects is not known. In addition, ROS activity directly results in dysfunction of the neuronal survival signaling pathway, Akt/PRAS40 pathway, and Akt dysfunction leads to inflammation. However, the roles of the Akt/PRAS40 pathway and inflammation in the protective effects of ischemic postconditioning have not been well studied. In this grant, we will first identify subcellular sources of ROS activity that are involved in postconditioning's protective effects. We will then study the relationship between ROS reduction and Akt/PRAS40 activity in both rats and PRAS40 knockout mice, which has never been used in any studies. Finally, we will study how Akt/PRAS40 regulates the inflammatory response, including its effects on the pro-inflammatory factors HMGB1 and Cox-2, and the novel galectin-9/Tim-3 inflammatory pathway. Through these studies, we will fill significant gaps in our knowledge about the protective mechanisms and clinical translation of ischemic postconditioning. Specific Aim 1. To identify the subcellular regulatory sources of ROS reduction that play critical roles in the protective effects of ischemic postconditioning. Specific Aim 2. To study whether ROS inhibition improves the Akt/PRAS40 activity. Specific Aim 3. To examine the protective effects of the Akt/PRAS40 pathway on the pro-inflammatory response of HMGB1 and Cox-2, and the galectin-9/Tim-3 inflammatory pathway. PUBLIC HEALTH RELEVANCE: Both rapid and delayed postconditioning after stroke reduce ischemic damage, opening up a new avenue for research in stroke treatment, which may eventually be clinically applicable for stroke patients.
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0.939 |