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. ? ? ?
| Baltan, Selva; Inman, Denise M; Danilov, Camelia A et al. (2010) Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration. J Neurosci 30:5644-52 |
