Model for Regulatiion of Gliosis in Glaucoma

描述(申请人提供)：我们对中枢神经系统中的神经胶质细胞的知识已经扩大，帮助研究人员理解神经胶质细胞不仅仅是神经元的支持细胞。胶质细胞为中枢神经系统组织提供结构，引导迁移细胞，调节细胞外环境中的神经递质，产生信号分子，维持突触连接，形成血脑屏障，监测环境，并以多种方式对损伤和疾病做出反应。神经胶质细胞对损伤的反应称为胶质细胞增生症，它涉及细胞内中间丝的上调，离子通道补体的变化，信号分子的分泌，也可以包括增殖。胶质化在慢性青光眼小鼠模型中早期发生，并且在所有胶质细胞群(M？ler胶质细胞、星形胶质细胞和小胶质细胞)中的反应程度是显著的。到目前为止，胶质细胞增生症对RGC健康和青光眼进展的积极或消极影响还没有研究过。胶质细胞增多症很可能是发出损伤开始的信号，也许是为了启动代偿机制，从而维持受损组织的功能，但也限制了组织的损害。我们建议通过缓和DBA/2小鼠的神经胶质反应来了解胶质细胞增多症在青光眼中所起的作用。DBA/2在两个基因上发生突变，导致色素分散和虹膜萎缩，进而导致房角关闭和继发性青光眼。这些小鼠的眼压随着色素的分散而升高。有许多信号通路参与了胶质细胞增生症的发展。核因子-？B 通过对细胞黏附分子iNOS、BDNF、1 COX-2的转录调控，以及通过促进神经胶质细胞向突起生长的非允许底物的转变，该途径与胶质增生症有关。2核因子-βB是一种异源二聚体转录因子，通过与I？B结合，保持在细胞质中。I？B-激酶复合体的磷酸化导致I？B泛素化，然后在蛋白酶体中降解，从而释放核因子-？B，使其移位到DNA中特定区域的细胞核。我们将通过利用我们的青光眼小鼠模型DBA/2J培育一只高表达显性阴性形式的I？B(核因子-B的抑制物)的小鼠，从而针对核因子-？B途径来减少青光眼中的胶质细胞增生。核因子-βB在中枢神经系统中的功能如此多样，因此有必要针对特定类型的细胞来靶向该通路。公共卫生相关性声明中枢神经系统进行性疾病，包括帕金森氏症、阿尔茨海默氏症、亨廷顿氏症和肌萎缩侧索硬化症，伴随着通常发生在神经细胞死亡之前的严重轴索病。这些疾病是大脑普遍衰老造成的日益昂贵和心理负担沉重的后果，而且由于我们人口的迅速老龄化而变得更加严重。像这些疾病一样，青光眼是一种轴突冷漠，通过视神经的进行性退化而失明。与脑部疾病一样，青光眼正变得越来越普遍，已经成为全球第三大致盲原因，影响到约7000万至8000万人。的确，与眼压本身相比，年龄是青光眼更重要的指标。青光眼的视力丧失会导致生活质量的急剧下降，这是与衰老相关的主要恐惧，与认知能力的丧失密切相关。因此，试图研究和理解青光眼轴突变性的潜在机制不仅从眼科的角度来看是有用的，而且从理解与一般神经元衰老相关的细胞病理的角度也是有用的。

DESCRIPTION (provided by applicant): Our knowledge of glial cells in the central nervous system has expanded, helping researchers understand that glia are much more than support cells for neurons. Glia provide structure to CNS tissue, guide migrating cells, regulate neurotransmitters in the extracellular milieu, produce signaling molecules, maintain synaptic connections, form the blood-brain barrier, monitor the environment and respond in myriad ways to injury and disease. Glial response to injury is called gliosis, and involves upregulation of intermediate filaments within the cell, changes in the complement of ion channels, secretion of signaling molecules and can also include proliferation. Gliosis occurs early in the chronic mouse model of glaucoma, and the magnitude of the response in all glial populations (M¿ller glia, astrocytes and microglia) is significant. As of yet, the positive or negative impact of gliosis on RGC health and the progression of glaucoma has not been studied. It is likely that gliosis works to signal commencement of injury, perhaps to initiate compensatory mechanisms that will allow maintainenance of function in injured tissue but also to limit tissue compromise. We propose to learn what role gliosis plays in glaucoma by tempering the glial response in the DBA/2 mouse. The DBA/2 has mutations in two genes that cause pigment dispersion and iris atrophy which in turn, lead to angle closure and secondary glaucoma. Intraocular pressure increases with pigment dispersion in these mice. There are numerous signaling pathways involved in gliosis development. The NF-?B pathway has been implicated in gliosis by its transcriptional control of cell adhesion molecules, iNOS, BDNF,1 COX-2 and by virtue of its role in promoting glia cells' transition to a nonpermissive substrate for neurite outgrowth.2 NF-?B is a heterodimeric transcription factor kept in the cytoplasm through binding to I?B. Phosphorylation of I?B by the I?B -kinase complex causes I?B to become ubiquitinated then degraded in the proteasome, thereby releasing NF-?B for it translocation to the nucleus where it binds specific regions in the DNA. We will target the NF-?B pathway to decrease gliosis in glaucoma by breeding a mouse overexpressing a dominant negative form of I?B (inhibitor of NF-?B) with our mouse model of glaucoma, the DBA/2J. NF-?B has such diverse function in the CNS that it is necessary to target the pathway in specific cell types. Public Health Relevance Statement Loss of function in progressive diseases of the central nervous system, including Parkinson's, Alzheimer's, Huntington's, and ALS, accompanies severe axonopathy that often precedes neuronal cell death. These diseases are an increasingly costly and psychologically onerous consequence of general senescence of the brain and are rendered more severe by the rapid aging of our population. Like these diseases, glaucoma is an axonapathy, blinding through the progressive degeneration of the optic nerve. And like diseases of the brain, glaucoma is becoming increasingly prevalent and already represents the third leading cause of blindness worldwide, affecting some 70-80 million individuals. Indeed age is a greater indicator for glaucoma than ocular pressure itself. Loss of vision in glaucoma contributes to a dramatic decrease in quality of life that is a primary fear associated with aging, hand-in-hand with loss of cognitive ability. Therefore, attempts to study and understand the underlying mechanisms of axonal degeneration in glaucoma are useful not only from an ophthalmological standpoint, but also from the perspective of understanding the cellular pathologies associated with general neuronal senescence.