Glaucoma is a disease characterized by irreversible damage of optic nerve affecting millions of Americans. Yet details of the underlying disease mechanism are still unclear. While recognizing the crucial role of intraocular pressure (IOP), autoregulation (AR) dysfunction has been proposed as a cause of circulatory aberrations in the optic nerve head (ONH) associated with glaucomatous optic neuropathy. Autoregulation in the normal ONH initiated by an ocular perfusion pressure change contains two phases: an initial dynamic phase (dAR) when vascular smooth muscles dilate and contract to adjust the vascular resistance in an attempt to return blood flow (BF) to its original level;and a later steady-state phase (sAR) when dynamic BF changes have equilibrated to a steady level. Due primarily to methodological limitations, most previous studies in human and experimental glaucoma have assessed only sAR and failed to detect AR dysfunction in the ONH. With a modified laser speckle flowgraphy device (LSFG) and newly established methods for measuring the dAR and sAR, this proposal will test the following central hypothesis: Chronic IOP elevation induces AR dysfunction in the ONH, which importantly contributes to the pathophysiology of glaucomatous ONH damage. This hypothesis will be tested in three Specific Aims.
Specific Aim 1 : To test the hypothesis that ONH dAR abnormalities develop early in the monkey experimental glaucoma model, that they precede sAR and bBF alterations and that they progress in parallel with clinical measures of ONH and RNFL structural disruption.
Specific Aim 2 : To test the hypothesis that the ONH AR abnormalities occurring in the monkey model of experimental glaucoma are a primary result of exposure to chronic IOP elevation rather than a secondary result of neurodegeneration. Specifically, we will test the prediction that AR abnormalities will not develop in two alternative, non-IOP-related, axonal injury models - optic nerve transection and intra-retinal laser axotomy.
Specific Aim 3 : the ONH tissues obtained from the animals studied in Specific Aims 1 and 2 will be used to carry out two postmortem histological studies: 3A) To assess regional BF in the monkey ONH using a state-of-the-art microsphere method and compare these measurements with the LSFG bBF estimates obtained immediately prior to sacrifice;and 3B) To test the hypothesis that AR dysfunction detected in vivo by LSFG is associated with derangement of the relationship between ONH astrocytes, lamina cribrosacytes and the blood vessels within the underlying laminar beams and peripapillary scleral beam insertions. In a follow up R01 proposal we expect to extend our investigation in: 1) clinical application by modifying the current techniques of dAR analysis to noninvasively so as to elicit a controlled ONH dAR response. 2) Characterization of ONH astrocytes and lamina cribrosacyte role in ONH AR using 3D electron microscopic reconstructions and fresh ONH tissue slice preparations. 3) To test the hypothesis of age-related alterations between astrocytes and capillary endothelial/pericytes in AR.
This project seeks evidence of autoregulation (AR) dysfunction in the optic nerve head and its role in pathogenesis of glaucoma as well as to develop and assess a method for its clinical detection. These developments will make the detection of AR dysfunction in human ocular hypertensive and glaucoma patients a credible goal and the presence of AR dysfunction a therapeutic target for the treatment of the disease.
|Fortune, Brad; Reynaud, Juan; Hardin, Christy et al. (2016) Experimental Glaucoma Causes Optic Nerve Head Neural Rim Tissue Compression: A Potentially Important Mechanism of Axon Injury. Invest Ophthalmol Vis Sci 57:4403-11|
|Fortune, Brad; Hardin, Christy; Reynaud, Juan et al. (2016) Comparing Optic Nerve Head Rim Width, Rim Area, and Peripapillary Retinal Nerve Fiber Layer Thickness to Axon Count in Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:OCT404-12|
|Ing, Eliesa; Ivers, Kevin M; Yang, Hongli et al. (2016) Cupping in the Monkey Optic Nerve Transection Model Consists of Prelaminar Tissue Thinning in the Absence of Posterior Laminar Deformation. Invest Ophthalmol Vis Sci 57:2598-611|
|Cull, Grant; Told, Reinhard; Burgoyne, Claude F et al. (2015) Compromised Optic Nerve Blood Flow and Autoregulation Secondary to Neural Degeneration. Invest Ophthalmol Vis Sci 56:7286-92|
|Wang, Lin; Cull, Grant A; Fortune, Brad (2015) Optic nerve head blood flow response to reduced ocular perfusion pressure by alteration of either the blood pressure or intraocular pressure. Curr Eye Res 40:359-67|
|Cao, Li; Wang, Lin; Cull, Grant et al. (2015) Alterations in molecular pathways in the retina of early experimental glaucoma eyes. Int J Physiol Pathophysiol Pharmacol 7:44-53|
|Fortune, Brad; Reynaud, Juan; Cull, Grant et al. (2014) The Effect of Age on Optic Nerve Axon Counts, SDOCT Scan Quality, and Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in Rhesus Monkeys. Transl Vis Sci Technol 3:2|
|Wang, Lin; Burgoyne, Claude F; Cull, Grant et al. (2014) Static blood flow autoregulation in the optic nerve head in normal and experimental glaucoma. Invest Ophthalmol Vis Sci 55:873-80|
|Wang, Lin; Cull, Grant; Burgoyne, Claude F et al. (2014) Longitudinal alterations in the dynamic autoregulation of optic nerve head blood flow revealed in experimental glaucoma. Invest Ophthalmol Vis Sci 55:3509-16|
|Yu, Jintao; Liang, Yi; Thompson, Simon et al. (2014) Parametric transfer function analysis and modeling of blood flow autoregulation in the optic nerve head. Int J Physiol Pathophysiol Pharmacol 6:13-22|
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