Potential use of a decoy peptide for hypoxia/ischemia treatment

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Neonatal hypoxic ischemia (H/I) is largely responsible for neonatal encephalopathy, which occurs in 2-4 out of 1000 births per year in the US. While the resulting mortality has decreased, there has been a corresponding increased rate of children developing serious neurological disorders, including motor and learning disabilities, cerebral palsy and seizures. Although the mechanisms underlying H/I-induced neuronal damage are not completely understood, it has repeatedly been proposed that excitotoxicity due to over-excitation of glutamate receptors plays a critical role. Identification of downstream events from glutamate receptor activation has been the object of intense investigation, and the calcium dependent protease calpain has been implicated in ischemia-induced neuronal damage. Metabotropic glutamate receptors have recently emerged as new players in ischemic neuronal death, although their roles remain controversial. Studies have focused on one of the metabotropic glutamate receptors, mGluR1, as this receptor activates two signaling cascades, one leading to neurodegeneration through the stimulation of phospholipase C, the synthesis of inositol-3-phosphate and the release of calcium from internal stores and another one linked to neuroprotection through the PI3K-Akt pathway. We recently found that NMDA receptor activation results in calpain-mediated truncation of the C- terminal domain of mGluR11, one of the isoforms of mGluR1. As a result of this truncation, mGluR11 loses its neuroprotective signaling, although it maintains a normal calcium signaling function. In other words, truncated mGluR11 becomes an exclusively "neurodegenerative receptors", suggesting the existence of a positive feedback loop linking NMDA receptors, calpain activation and mGluR1 in excitotoxicity and neurodegeneration. Furthermore, we found that a small peptide consisting in a sequence of amino acids surrounding the cutting site linked to the HIV tat-peptide was neuroprotective against excitotoxicity both in vitro and in vivo. This R21 application is therefore directed at obtaining in vivo preclinical data to develop the tat-mGluR1 peptide or a modified form of this peptide for therapeutic use against neonatal H/I-induced neuronal damage. We will therefore test the potential neuroprotective effects of the tat-mGluR1 peptide in an in vitro and an in vivo model of neonatal H/I (Specific Aim #1). We will design and test the neuroprotective effects of analogs of tat-mGluR1 (Specific Aim #2). Positive results will then encourage the clinical development of this approach for the treatment of neonatal hypoxia/ischemia. PUBLIC HEALTH RELEVANCE: The rationale for the proposed studies is derived from recent studies in the PI's laboratory that have identified a new mechanism for excitotoxic neuronal damage as well as a promising neuroprotective peptide. This new mechanism involves the existence of a previously unknown positive feedback loop linking several molecular processes postulated to participate in glutamate-mediated neuronal death. The proposed studies will evaluate the neuroprotective effects of the peptide in an in vitro and an in vivo model of neonatal hypoxic/ischemic neuronal damage. If the peptide shows neuroprotective effects when applied after the hypoxic/ischemic insults, these studies will provide the in vivo proof-of-concept needed to pursue the clinical development of this approach not only for neonatal hypoxia/ischemia-induced neuronal damage, but also for neuronal damage occurring in other forms of neurodegenerative diseases.