2008 — 2021 |
Libby, Richard T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cell Death Pathways in Glaucomatous Neurodegeneration @ University of Rochester
DESCRIPTION (provided by applicant): Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells (RGCs). Axonal injury is an important, early insult to RGCs in glaucoma and axonal damage precedes cell body degeneration. Identifying the local axonal signaling pathways that initiate these changes is an important step in understanding glaucoma and other axonopathies. Following axonal injury, phosphorylation-dependent signal relay events are among the first changes to occur and these signals likely trigger fate-determining events in the axon and cell body. The mitogen-activated protein kinase (MAPK) family plays an integral role in signal transduction in response to changes in the cellular environment by integrating diverse signals arising from cellular stressors and initiating changes in gene expression. c-Jun N-terminal kinases, (JNK1-3) are MAPK family members that are known to be involved in axonal injury signaling. JNK activation is known to occur in human glaucoma patients and has been documented in various glaucoma models. We have shown that the JNKs are activated in RGC axons soon after injury and those they are important mediators of axonal injury-induced RGC death. Furthermore, we have shown that RGC death is dependent on activation of the canonical JNK substrate, the transcription factor JUN. In this application we propose a series of experiments designed to define a key axonal injury pathway-JNK signaling-in glaucomatous neurodegeneration and to test our central hypothesis: A JNK signaling pathway is a critical mediator of RGC death after axonal injury and is the signaling pathway that links axonal injury to RGC death. Specifically, we will determine: 1) the JNK dependent events that control RGC death after a glaucomatous injury; 2) whether activation of the transcription factor JUN is required for glaucomatous RGC death; and 3) the identity of the axonal injury-induced kinases that control JNK activation and axon degeneration in glaucoma. Since axonal injury and degeneration are likely to be key events in glaucoma and JNK signaling is active in glaucomatous eyes, understanding this pathway will be important for understanding the pathophysiology of glaucoma. The experiments outlined in this application will: define new molecules fundamental in the axonal injury and degeneration cascade, identify molecular events that are early in the injury signaling cascade which are ideal targets for therapeutic intervention and define the critical pathological insults that trigger axonal injury and degeneration in glaucoma.
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2017 — 2021 |
Howell, Gareth R Libby, Richard T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cell Specific Roles of the Endothelin System in Glaucoma-Relevant Retinal Ganglion Cell Death @ University of Rochester
Glaucoma is an optic neuropathy characterized by retinal ganglion cell (RGC) death and optic nerve degeneration. Unfortunately, there are no current treatments that specifically target neurodegeneration. Identifying the signaling pathways responsible for disease onset and progression will be an important step in developing effective pharmacologic interventions for glaucomatous neurodegeneration. The endothelin (EDN) system is widely expressed throughout the body and participates in both physiological and pathophysiological processes. There is now a large body of evidence implicating the EDN system in human and in animal models of glaucoma. Manipulation of the EDN system significantly lessens RGC loss in a genetic and two inducible models of glaucoma. Also EDN signaling is upregulated in both the retina and optic nerve head prior to any signs of RGC death or dysfunction in an ocular hypertensive model of glaucoma. Despite the potential importance of EDN in glaucomatous neurodegeneration, the molecular mechanisms of EDN-induced RGC death are completely undefined. In particular, the upstream regulators and the downstream effectors of the EDN system are not known. Contributing to the difficulty in understanding how EDN signaling plays a role in glaucomatous neurodegeneration is the fact that EDN receptors, Ednra and Ednrb, are expressed on numerous cell types in the retina and optic nerve head including RGCs, astrocytes, myeloid derived cells (microglia and macrophages), and mural cells (pericytes and smooth muscle vascular cells). Furthermore, EDN is known to affect all of these cells in ways that are consistent with pathological responses observed in glaucoma. Thus, in order to understand EDN signaling in glaucoma the requirement of components of the EDN system, both receptors and ligands, must be systematically tested in the glaucoma-relevant cells they are expressed in. Here, we will test the hypothesis that defining the role of the EDN system in RGC death will identify early, critical signaling pathways that underlie glaucoma pathogenesis. To accomplish this and to define how EDN signaling functions after glaucoma-relevant insults, we will 1) define the mechanisms within RGCs that are required for EDN-induced RGC death, 2) determine the receptor, cell type, and molecular pathway(s) controlling EDN-induced RGC death, and 3) determine which cell types and molecular pathways are responsible for producing pathogenic EDN ligands. Importantly, this application will focus on the role of the EDN system in individual cell types, conditionally removing EDN components and performing transcriptomics on individual cell types. Together, the experiments outlined in the application critically test a long-standing hypothesis about the role of EDN in glaucoma and identify the various cell types and molecular mechanisms controlling glaucoma-relevant pathogenic EDN signaling. Given the early nature and proven role of EDN signaling in glaucomatous neurodegeneration these experiments will identify novel targets for developing neuroprotective treatments for glaucoma at early stages of disease pathogenesis.
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