Energy metabolism in all mammalian retinal cells is linked with demand for ions such as calcium. This metabolic-ion demand axis plays a central role in normal retinal function and hence healthy vision. Loss of vision and blindness are associated with the appearance of retinal neovascularization (NV) in diseases such as retinopathy of prematurity (ROP) and diabetic retinopathy. The pathophysiology associated with retinal NV is not well understood, although neuronal dysfunction and perturbed ion homeostasis have both been suggested as important factors. It is not yet known if abnormal ion demand occurs before the appearance of retinal NV and in retinal regions that give rise to retinal NV. These temporal and spatial knowledge gaps can not be addressed at present because current methods lack either spatial specificity (e.g., electroretinogram) or the ability to provide functional metrics of ion demand in vivo (histology). We propose a novel method to non-invasively measure retinal layer-specific ion demand that can also be applied in experimental rodent models of NV. This method, manganese-enhanced MRI (MEMRI), takes advantage of the facts that manganese (Mn2+) ion is a surrogate biomarker for various ions including calcium, and is a strong MRI contrast agent. We have validated that known retinal layer-specific changes in neuronal function / ion demand during light and dark adaptation can be robustly measured by high resolution MEMRI following systemic administration of a non-toxic amount of MnCl2 to awake rodents. Our overlying hypothesis is that the appearance of retinal NV will be temporally and spatially linked with abnormal neuronal function, as assessed by perturbed manganese uptake.
Aim 1 : To test the prediction that retinal NV in rat and mouse models is linked with abnormal Mn2+ uptake (indicative of perturbed ion demand) at the border of vascular and avascular retina (i.e., the site of retinal NV). The results of this innovative research will help clarify whether or not abnormal ion demand plays an important role in the development of preretinal NV. The novel methods in this application will also contribute to the advancement of functional MRI for the study of retinal diseases. The results of this innovative research will help clarify whether or not abnormal ion demand plays an important role in the development of preretinal neovascularization, a major cause of vision loss and blindness in premature births and diabetes. The novel methods in this application will also contribute to the advancement of functional MRI for the study of retinal diseases. ? ? ?
|Bissig, David; Berkowitz, Bruce A (2014) Testing the calcium hypothesis of aging in the rat hippocampus in vivo using manganese-enhanced MRI. Neurobiol Aging 35:1453-8|
|Berkowitz, Bruce A; Bissig, David; Dutczak, Oliver et al. (2013) MRI biomarkers for evaluation of treatment efficacy in preclinical diabetic retinopathy. Expert Opin Med Diagn 7:393-403|
|Bissig, David; Goebel, Dennis; Berkowitz, Bruce A (2013) Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx. PLoS One 8:e56340|
|Bissig, David; Berkowitz, Bruce A (2012) Light-dependent changes in outer retinal water diffusion in rats in vivo. Mol Vis 18:2561-xxx|
|Braun, Rod D; Bissig, David; North, Robert et al. (2012) Human tumor cell proliferation evaluated using manganese-enhanced MRI. PLoS One 7:e30572|
|Berkowitz, Bruce A; Bissig, David; Ye, Yongquan et al. (2012) Evidence for diffuse central retinal edema in vivo in diabetic male Sprague Dawley rats. PLoS One 7:e29619|
|Berkowitz, Bruce A; Bissig, David; Bergman, Deborah et al. (2011) Intraretinal calcium channels and retinal morbidity in experimental retinopathy of prematurity. Mol Vis 17:2516-26|
|Bissig, David; Berkowitz, Bruce A (2011) Same-session functional assessment of rat retina and brain with manganese-enhanced MRI. Neuroimage 58:749-60|
|Wang, Qing; Song, Sheng-Kwei; Zhang, Huiying et al. (2011) Photoreceptor degeneration changes magnetic resonance imaging features in a mouse model of retinitis pigmentosa. Magn Reson Med 65:1793-8|
|Berkowitz, Bruce A; Roberts, Robin; Bissig, David (2010) Light-dependant intraretinal ion regulation by melanopsin in young awake and free moving mice evaluated with manganese-enhanced MRI. Mol Vis 16:1776-80|
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