Modulators of Retinal Injury

描述（由申请人提供）：我们的团队对视网膜对损伤的反应感兴趣。最近，我们扩展了我们的方法，使用微阵列和生物信息学来观察转录组的大部分。在这个过程中，一个独特的引人注目的机会将我们的集体兴趣集中在一个项目上，该项目以小鼠视网膜轴突损伤（视神经挤压）为模型系统。在与罗布·威廉姆斯小组的合作中，我们正在使用BXD重组近交（Rl）菌株来定义眼睛和视网膜中的遗传网络。这些相互作用使我们处于一个独特的位置，可以研究视网膜损伤的早期特征和可能是视神经损伤易感性或抗性基础的基因组位点。该项目的长期目标是确定控制视网膜对视神经损伤的易感性和抗性的遗传网络，并描述与这些变化相关的早期分子特征。我们的工作假设是，视网膜的不同易感性是由多态基因网络调节的，多态基因网络有助于神经变性和神经节细胞死亡的易感性或抗性。我们将使用一组独特的等基因小鼠（BXD Rl菌株）来研究视神经损伤的实验模型。这一大组菌株特别适合研究视神经损伤的遗传学，因为亲本菌株之一易受损伤（DBA/2J菌株），而另一株具有抗性（C57BL/6菌株）。这项工作在三个特定的目标中利用了这种特殊应变面板的独特特性。目的1将定义正常模式的转录活性在视网膜重组近交系株。在这些未受伤小鼠中发现的转录网络将作为视神经损伤后发生变化的背景。Aim 2将验证BXD Rl菌株视网膜中存在一系列转录组特征的假设，这些转录组特征可预测轴突损伤后神经节细胞死亡的易感性或抗性。这些数据将定义视神经轴突损伤后激活的常见和独特的遗传网络，并将定义与视神经损伤相关的早期变化。最后，我们将能够识别控制神经节细胞死亡的易感性和抗性的遗传网络。

DESCRIPTION (provided by applicant): Our group is interested in the response of the retina to injury. Recently we expanded our approach looking at a large segment of the transcriptome using microarrays and bioinformatics. During this process a unique compelling opportunity focused our collective interest on a project looking at retinal axon damage (optic nerve crush) in the mouse as a model system. In collaboration with the Rob Williams' group we are using the BXD recombinant inbred (Rl) strains to define genetic networks in the eye and retina. These interactions have put us in a unique position to study the early signature of retinal injury and genomic loci that may underlie susceptibility or resistance to optic nerve damage. The long-term goal of this project is to define genetic networks controlling susceptibility and resistance of the retina to optic nerve damage and to characterize the early molecular signatures associated with these changes. Our working hypothesis is that the differential vulnerability of the retina is modulated by network of polymorphic genes that contribute to susceptibility or resistance to neurodegeneration and ganglion cell death. We will use a unique set of isogenic strains of mice (the BXD Rl strains) to investigate an experimental model of optic nerve damage. This large set of strains is uniquely suited to study the genetics of optic nerve damage because one of the parental strains is susceptible to injury (DBA/2J strain) whereas the other strain is resistant (C57BL/6 strain). This work exploits the unique properties of this particular strain panel in three specific aims. Aim 1 will define the normal patterns of transcriptional activity in the retinas of recombinant inbred strains. The transcriptional networks identified in these uninjured mice will serve as a background to define the changes occurring after optic nerve damage. Aim 2 will test the hypothesis that there are a series of transcriptome signatures in the retina of the BXD Rl strains that are predictive of susceptibility or resistance of ganglion cell death after axon injury. These data will define the common and unique genetic networks that are activated following injury to the optic nerve axons and will define the early changes associated with optic nerve damage. Finally we will be able to identify the genetic networks controlling susceptibility and resistance to ganglion cell death.