Model for Regulatiion of Gliosis in Glaucoma

描述（由申请人提供）：我们对中枢神经系统中神经胶质细胞的了解已经扩大，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。神经胶质对损伤的反应被称为神经胶质增生，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，还可以包括增殖。神经胶质增生在慢性小鼠青光眼模型中早期发生，并且所有神经胶质细胞群（M？ller神经胶质细胞、星形胶质细胞和小神经胶质细胞）中的反应幅度是显著的。到目前为止，神经胶质增生对RGC健康和青光眼进展的积极或消极影响尚未研究。神经胶质增生很可能是损伤开始的信号，也许是启动补偿机制，使受损组织的功能恢复，但也限制组织损害。我们建议通过调节DBA/2小鼠的神经胶质反应来了解神经胶质增生在青光眼中的作用。DBA/2有两个基因突变，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。在这些小鼠中，眼内压随着色素分散而增加。有许多信号通路参与神经胶质增生的发展。NF-？B NF-κ B通路通过其对细胞粘附分子iNOS、BDNF、1考克斯-2的转录调控，并通过其在促进神经胶质细胞向神经突生长的非允许底物转变中的作用，与神经胶质增生有关。B是一个异源二聚体转录因子，通过与I？B。I的磷酸化？I边的B？B -激酶复合物引起I？B被泛素化，然后在蛋白酶体中降解，从而释放NF-？B，使其易位到细胞核，在那里它结合DNA中的特定区域。我们要瞄准NF-？B途径通过繁殖过表达I？B（NF-？B）用我们的青光眼小鼠模型，DBA/2 J. NF-？B在CNS中具有如此多样的功能，以至于有必要在特定细胞类型中靶向该途径。公共卫生相关性声明中枢神经系统进行性疾病（包括帕金森氏病、阿尔茨海默氏病、亨廷顿病和ALS）的功能丧失伴随严重的轴突病，通常在神经元细胞死亡之前发生。这些疾病是大脑普遍衰老的后果，代价越来越高，心理负担越来越重，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症，通过视神经的进行性变性致盲。与脑部疾病一样，青光眼正变得越来越普遍，并已成为全球第三大致盲原因，影响约7000万至8000万人。事实上，年龄是青光眼的一个更大的指标，比眼压本身。青光眼中的视力丧失导致生活质量急剧下降，这是与衰老相关的主要恐惧，与认知能力丧失密切相关。因此，尝试研究和理解青光眼中轴突变性的潜在机制不仅从眼科学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学的角度来看也是有用的。

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.