A transgenic model to study Bif-1 mediated neuroprotection in injury and disease

描述（由申请人提供）：越来越多的证据表明，线粒体功能障碍与影响大脑的损伤和疾病所观察到的神经退行性变既有关联，也有因果关系。虽然能量代谢和ATP产生的紊乱受到了极大的关注，但线粒体动力学的调节也发现了异常，这涉及到影响线粒体形状和大小的融合和裂变（断裂）过程。重要的是，线粒体的融合和裂变直接参与确保它们的正确分布、运输和周转。考虑到神经元在能量需求部位拥有健康的线粒体是多么重要，不难想象，损害线粒体裂变和融合调节的遗传或表观遗传修饰可能会产生不利影响

DESCRIPTION (provided by applicant): Accumulating evidence demonstrates that mitochondrial dysfunction is both associated with and causally related to neurodegeneration observed in response to injury and diseases affecting the brain. While disturbances in energy metabolism and ATP production have received significant attention, abnormalities are also being found in the regulation of mitochondrial dynamics which involves the processes of fusion and fission (fragmentation) affecting the shape and size of mitochondria. Importantly, mitochondrial fusion and fission are directly involved in ensuring their proper distribution, transport, and turnover. Considering how vital it is for neurons to have healthy mitochondria positioned at sites of energy demand, it is not difficult to imagine that genetic or epigenetic modifications that impair the regulation of mitochondrial fission and fusion could adversely affect neuronal connectivity, function and viability. We recently determined that neurons express two alternatively spliced forms of a mitochondrial fission regulating protein, Bif-1 (Bif-1b/c). Our preliminary data demonstrates that Bif-1b/c is lost in neurons in the penumbra (cerebral cortex) of mice subjected to middle cerebral artery occlusion (MCAO, stroke model). Importantly, the Bif-1-null condition enhanced neuronal cell death caused by MCAO, and DNA damage and Abeta cytotoxicity in culture. Conversely, Bif-1c overexpression confers significant protection against Abeta-mediated toxicity indicating that Bif-1 is required for normal neuronal function. The Bif-1b/c protein is significantly reduced in the parietal cortex (affected area) and in synaptosomes of sporadic Alzheimer's disease (AD) patients compared to aged matched non-AD patients. These changes in Bif-1b/c are also observed in the APPswe/PS1dE9 mouse AD model and in primary cortical neurons following addition of the toxic Abeta peptide. Moreover, in preliminary studies, Bif-1-null mice displayed significant cognitive impairment at one year of age and knockout of the Bif-1 homologue (endoB) in drosophila enhanced the toxicity of the toxic Abeta42 peptide based on an eye phenotype, but had no effect on flies expressing the non-toxic Abeta40 peptide. These findings demonstrate a potential neuroprotective function of Bif-1 and suggest that mitochondrial dysfunction associated with ischemic damage and AD may be due to reduced expression of Bif-1b/c. We propose to test the hypothesis that restoration of Bif-1c expression in neurons in an inducible transgenic mouse promotes neuronal survival, retention of mitochondrial integrity and enhances cognitive function in response to stroke and in a mouse model of AD. These studies will determine if Bif-1c has therapeutic actions for reducing injury and disease-induced damage.