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，帮助研究人员了解神经胶质细胞不仅仅是神经元的支持细胞。神经胶质细胞为中枢神经系统组织提供结构，引导细胞迁移，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作出反应。胶质细胞对损伤的反应被称为胶质细胞增生，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，也可能包括增殖。胶质瘤发生在慢性青光眼小鼠模型的早期，所有胶质细胞群（M¿ller胶质细胞、星形胶质细胞和小胶质细胞）的反应幅度都是显著的。到目前为止，胶质瘤对RGC健康和青光眼进展的积极或消极影响尚未得到研究。神经胶质瘤可能是损伤开始的信号，可能启动补偿机制，使受损组织的功能得以维持，但也限制了组织的损害。我们建议通过调节DBA/2小鼠的神经胶质反应来了解胶质瘤在青光眼中的作用。DBA/2有两个基因突变，导致色素分散和虹膜萎缩，进而导致闭角和继发性青光眼。眼压随着色素的分散而升高。胶质细胞形成过程中有许多信号通路。NF - ?B

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.