Modulators of Retinal Injury

描述(申请人提供)：我们的团队对视网膜损伤的反应感兴趣。最近，我们扩展了我们的方法，使用微阵列和生物信息学研究了转录组的一大部分。在这个过程中，一个独特的令人信服的机会将我们的集体兴趣集中在一个项目上，该项目将小鼠的视网膜轴突损伤(视神经挤压)作为一个模型系统。在与Rob Williams团队的合作中，我们正在使用BXD重组近交系(RL)菌株来定义眼睛和视网膜的遗传网络。这些相互作用使我们处于一个独特的位置来研究视网膜损伤的早期特征和可能导致视神经损伤易感性或抵抗力的基因组位点。该项目的长期目标是确定控制视网膜对视神经损伤的敏感性和抵抗力的遗传网络，并表征与这些变化相关的早期分子特征。我们的工作假设是，视网膜的不同脆弱性是由多态基因网络调节的，这些多态基因有助于对神经变性和神经节细胞死亡的易感性或抵抗力。我们将使用一组独特的等基因小鼠品系(BXD RL品系)来研究视神经损伤的实验模型。这一大组菌株特别适合于研究视神经损伤的遗传学，因为其中一个亲本菌株(DBA/2J菌株)对损伤敏感，而另一个菌株(C57BL/6菌株)具有抗性。这项工作在三个特定的目的中利用了这种特殊应变面板的独特属性。目的1将确定重组近交系的视网膜转录活性的正常模式。在这些未受损伤的小鼠中发现的转录网络将作为定义视神经损伤后发生的变化的背景。目的2验证BXD RL株视网膜中存在一系列转录组信号的假说，这些转录组信号预测轴突损伤后神经节细胞死亡的易感性或抵抗性。这些数据将定义视神经轴突损伤后被激活的共同和独特的遗传网络，并将定义与视神经损伤相关的早期变化。最后，我们将能够确定控制神经节细胞死亡的易感性和抵抗力的遗传网络。

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.