The role of NFkB in glia-neuron crosstalk in glaucoma

描述（由申请人提供）：我们的长期目标是开发一种全面的基于信息学的方法，以了解细胞相互作用中的病理变化如何促进疾病。为了将先进的信息学应用于视网膜病理学的研究，我们开发了有效的纯化和特征分析初级神经元和神经胶质细胞的方法，这两种细胞类型在视网膜中密切相互作用。在这个R21项目中，我们将测试我们的方法的可行性，使用来自眼内压升高的眼睛的视网膜细胞，青光眼的小鼠模型。已经确定，在暴露于升高的眼内压的视网膜中，重要的神经胶质-神经元相互作用的显著失调促进视网膜神经元（RGC）的死亡，这是青光眼中失明的原因。我们将在具有遗传改变的神经胶质细胞的小鼠中引发青光眼，以研究促进这些动物中RGC存活增加的分子相互作用。信息学软件工具将有助于将大量的分子数据转换为简洁的假设，可视化为描绘细胞机器受影响“部分”的图形网络。这项研究的结果将建立我们的基于信息学的方法来研究视网膜中的致病细胞相互作用的可行性。这些结果将为青光眼中靶向胶质细胞的治疗策略提供候选途径。该项目开发了新的分子和生物信息学策略，以解决青光眼中神经胶质细胞如何影响视网膜神经节细胞存活的临床重要问题。虽然神经胶质活化对视网膜的稳态是有害的，但分析和恢复这种不平衡的方法目前仍未开发。将在此测试的方法和将在此可行性研究中获得的结果可用于搜索和测试青光眼的新的潜在治疗靶点。

DESCRIPTION (provided by applicant): Our long-term goal is to develop a comprehensive informatics-based approach to understand how pathological change in cell interactions promotes disease. To apply an advanced informatics to the research of retinal pathologies we developed efficient methods of purification and signature profiling primary neurons and glia, two closely interacting cell types in the retina. In this R21 project, we will test the feasibility of our approach using retinal cells derived from the eyes with elevated intraocular pressure, a mouse model of glaucoma. It is established that in the retina exposed to the elevated intraocular pressure a dramatic dysregulation in the vital glia-neuronal interaction promotes death of retinal neurons (RGCs), the cause of blindness in glaucoma. We will initiate glaucoma in the mice with genetically altered glial cells to study molecular interactions facilitating an increased survival of the RGCs in these animals. Informatics software tools will help converting an overwhelming amount of molecular data into concise hypothesis, visualized as graphical networks depicting the affected "parts" of cellular machinery. The results of this study will establish feasibility of our informatics-based approach to study pathogenic cell interactions in the retina. The results will provide candidate pathways for a therapeutical strategy targeting glial cells in glaucoma. This project develops novel molecular and bioinformatics strategies to address clinically important question of how the glial cells impact retinal ganglion cell survival in glaucoma. Although glial activation is detrimental to the homeostasis of the retina, methods to analyze and restore such imbalances remain currently undeveloped. The methodology that will be tested here and the results that will be obtained in this feasibility study can be utilized to search for and test new potential therapeutic targets for glaucoma.