Decades of research on post-mortem tissue have suggested a pathogenic role of rod cell oxidative stress in blinding disorders, such as diabetic retinopathy (DR) and retinitis pigmentosa (RP). Confirming this hypothesis in vivo, and demonstrating clinical potential in experimental models, requires the currently unrealized ability to noninvasively measure rod cell oxidative stress using endogenous contrast mechanisms in vivo. Here, we demonstrate that 25 ?m axial resolution MRI 1/T1 transretinal mapping is sufficiently sensitive to measure in control mice continuous production of endogenous paramagnetic free radicals from rod photoreceptor cells in the dark compared to two quench conditions, light or pharmacologic suppression of the production of mitochondrial free radicals. In a disease linked with rod oxidative stress, diabetes, rod free radical productions is greater than normal and is associated with co-localized MRI measures of rod dysfunction in vivo. Our overriding hypothesis is that measuring both rod free radical production and several essential rod functions in vivo provides an index of the severity of rod oxidative stress over time in both DR and RP that will be predictive of progression of both diseases, as well as allow for assessment of the efficacy of anti-oxidant therapy on disease outcome. The results of the proposed experiments will directly and unambiguously measure rod oxidative stress burden in incipient DR and RP in vivo, and this will enable earlier evaluation of disease progression and anti-oxidant treatment efficacy than is currently possible. Most of our new assays of rod free radical production and function are based on endogenous contrast mechanisms which greatly facilitate their translation into patients with DR and RP, and other oxidative-stress-based retinal diseases.
Berkowitz, Bruce A. The proposed research is relevant to public health because current imaging methods cannot measure in vivo rod cell oxidative stress, a major pathogenic factor in diseases such as diabetic retinopathy (DR) and retinitis pigmentosa (RP). The results of the proposed experiments will directly measure rod oxidative stress burden in incipient DR and RP in vivo, based on the combined evaluation of free radical production together with their essential functions of light detection, regulated transmission of information, and visual pigment regeneration, and this new ability will enable earlier evaluation of disease progression and anti-oxidant treatment efficacy than is currently possible. Most of our new assays of rod free radical production and function are based on endogenous contrast mechanisms which will greatly facilitate their translation into patients with DR and RP, and other oxidative-stress-based retinal diseases.
|Berkowitz, Bruce A; Podolsky, Robert H; Berri, Ali M et al. (2018) Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6brd10 Mice. Invest Ophthalmol Vis Sci 59:1659-1665|
|Huereca, Daniel J; Bakoulas, Konstandinos A; Ghoddoussi, Farhad et al. (2018) Development of manganese-enhanced magnetic resonance imaging of the rostral ventrolateral medulla of conscious rats: Importance of normalization and comparison with other regions of interest. NMR Biomed 31:|
|Berkowitz, Bruce A; Podolsky, Robert H; Qian, Haohua et al. (2018) Mitochondrial Respiration in Outer Retina Contributes to Light-Evoked Increase in Hydration In Vivo. Invest Ophthalmol Vis Sci 59:5957-5964|
|Berkowitz, Bruce A (2018) Oxidative stress measured in vivo without an exogenous contrast agent using QUEST MRI. J Magn Reson 291:94-100|
|Berkowitz, Bruce A; Lenning, Jacob; Khetarpal, Nikita et al. (2017) In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J 31:4179-4186|
|Berkowitz, Bruce A; Podolsky, Robert H; Lenning, Jacob et al. (2017) Sodium Iodate Produces a Strain-Dependent Retinal Oxidative Stress Response Measured In Vivo Using QUEST MRI. Invest Ophthalmol Vis Sci 58:3286-3293|
|Berkowitz, Bruce A; Miller, Richard A; Roberts, Robin (2017) Genetically heterogeneous mice show age-related vision deficits not related to increased rod cell L-type calcium channel function in vivo. Neurobiol Aging 49:198-203|
|Berkowitz, Bruce A; Schmidt, Tiffany; Podolsky, Robert H et al. (2016) Melanopsin Phototransduction Contributes to Light-Evoked Choroidal Expansion and Rod L-Type Calcium Channel Function In Vivo. Invest Ophthalmol Vis Sci 57:5314-5319|