The fundamental gap in understanding endogenous neuroprotection evoked by ischemic tolerance impedes identification of therapeutic targets for retinal ischemia, a major cause of visual loss. Involvement of inflammation, glial activation, oxidative stress, and neurodegeneration in chronic retinal ischemic diseases such as diabetic retinopathy, suggests a primary role for neuroprotection. The long-term goal is to decipher the mechanisms of endogenous ischemic tolerance, as an innovative modulator of ischemic injury. The overall objective is to understand the activation, control, and downstream mechanisms of two key proteins, Akt and p38, in ischemic tolerance. The central hypothesis is that their activation, individually or together, drives retinal endogenous tolerance. Underlying the hypothesis is the applicant's results in a rat model wherein p38 evoked, while blocking specific Akt subtypes, attenuated ischemic tolerance. Akt or p38 knockdown inhibited the conceptually-related post-ischemic conditioning (transient ischemia after the damaging ischemia). Rationale for the proposal is that, after understanding these signaling mechanisms, the pathways can be precisely tuned, potentially translating into effective treatment for the >10 million/year at risk for retinal ischemia. The central hypothesis will be tested in three specific aims: 1) Identify p38 neuroprotective signaling, 2) Identify Akt neuroprotective signaling, 3) Determine mechanisms of delayed post-ischemic conditioning related to p38 and Akt.
In Aim 1, an established RNA interference approach (siRNA) will examine p38's control and downstream mechanisms in ischemic tolerance.
In Aim 2, siRNA will block Akt, and a novel Akt phosphomimetic viral vector whose efficacy is supported by preliminary data, will over express Akt subtypes. Measuring substrates of Akt subtypes, and pathway cross-talk will illuminate the mechanisms of neuroprotection.
In Aim 3, using the PI's delayed retinal ischemic post-conditioning model, examination of Akt, p38, and downstream mediators will elucidate the mechanisms of restoration of post-ischemic neuronal function. Experimental outcomes will be measured in Aims 1-3 by modern, validated molecular and physiological approaches that are well established in the applicant's lab. Innovatively exploiting endogenous neuroprotection by providing ischemic tolerance will yield novel targets to treat ischemic disease by engaging cell survival mechanisms. The proposed research is significant because it is expected to vertically advance and expand understanding of how the retina's endogenous cellular machinery can be harnessed to prevent or treat ischemia, while increasing understanding of cell survival signaling in vivo. Ultimately, this knowledge has potential to transform treatment of retinal ischemia by identifying novel, specific molecular interventional targets that will help to decrease the growing problem of visual loss and disability from ischemic disease in the retina.
Retinal ischemia is a common cause of visual impairment and blindness. The proposed research is relevant to public health because identifying the mechanisms of endogenous retinal ischemic tolerance mediated by protein kinas-related signaling is ultimately expected to stimulate development of safe, effective, and innovative treatment or prevention strategies for people at risk for ischemic diseases, as well as enhanced understanding of cellular signaling in vivo. Thus the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.
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